U.S. patent application number 15/083879 was filed with the patent office on 2016-09-01 for hydrophobic drug-delivery material, method for manufacturing thereof and methods for delivery of a drug-delivery composition.
The applicant listed for this patent is Scott Hampton, Joerg Kriwanek, Sonja Lehmann, Andreas Reiff, Andreas Voigt. Invention is credited to Scott Hampton, Joerg Kriwanek, Sonja Lehmann, Andreas Reiff, Andreas Voigt.
Application Number | 20160250146 15/083879 |
Document ID | / |
Family ID | 47278295 |
Filed Date | 2016-09-01 |
United States Patent
Application |
20160250146 |
Kind Code |
A1 |
Voigt; Andreas ; et
al. |
September 1, 2016 |
Hydrophobic Drug-Delivery Material, Method for Manufacturing
Thereof and Methods for Delivery of a Drug-Delivery Composition
Abstract
A method for manufacturing a drug-delivery composition includes
providing at least a pharmaceutically active composition, providing
a hydrophobic matrix; and mixing the hydrophobic matrix and the
pharmaceutically active composition to form a paste-like or
semi-solid drug-delivery composition.
Inventors: |
Voigt; Andreas; (Berlin,
DE) ; Hampton; Scott; (Tarpon Springs, FL) ;
Reiff; Andreas; (San Marino, CA) ; Lehmann;
Sonja; (Berlin, DE) ; Kriwanek; Joerg;
(Berlin, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Voigt; Andreas
Hampton; Scott
Reiff; Andreas
Lehmann; Sonja
Kriwanek; Joerg |
Berlin
Tarpon Springs
San Marino
Berlin
Berlin |
FL
CA |
DE
US
US
DE
DE |
|
|
Family ID: |
47278295 |
Appl. No.: |
15/083879 |
Filed: |
March 29, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13307506 |
Nov 30, 2011 |
9364549 |
|
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15083879 |
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Current U.S.
Class: |
424/489 |
Current CPC
Class: |
A61K 9/14 20130101; A61K
47/44 20130101; A61P 7/02 20180101; A61P 29/00 20180101; A61K 47/14
20130101; A61P 25/24 20180101; A61K 47/02 20130101; A61P 9/10
20180101; A61K 39/395 20130101; A61K 39/00 20130101; A61K 47/46
20130101; A61P 37/04 20180101; A61K 2039/505 20130101; A61P 31/00
20180101; A61P 9/12 20180101; A61K 47/22 20130101; A61P 37/06
20180101; A61P 31/10 20180101; A61P 9/06 20180101; A61K 47/10
20130101; A61P 23/00 20180101; A61P 25/08 20180101; A61K 9/06
20130101; A61P 37/08 20180101; A61K 47/12 20130101; C07K 16/00
20130101 |
International
Class: |
A61K 9/06 20060101
A61K009/06; A61K 47/10 20060101 A61K047/10; C07K 16/00 20060101
C07K016/00; A61K 47/12 20060101 A61K047/12; A61K 47/14 20060101
A61K047/14; A61K 39/395 20060101 A61K039/395; A61K 47/44 20060101
A61K047/44 |
Claims
1. A method for manufacturing a drug-delivery composition,
comprising: providing at least a pharmaceutically active
composition; providing a hydrophobic matrix; and mixing the
hydrophobic matrix and the pharmaceutically active composition to
form a paste-like or semi-solid drug-delivery composition.
2. The method according to claim 1, wherein providing the
hydrophobic matrix comprises mixing of at least a hydrophobic solid
component and a hydrophobic liquid component.
3. The method according to claim 1, further comprising: providing
the pharmaceutically active composition as dry pharmaceutically
active composition powder; and homogeneous mixing the hydrophobic
matrix with the dry pharmaceutically active composition powder to
form the paste-like or semi-solid drug delivery composition.
4. The method according to claim 1, further comprising: providing
the pharmaceutically active composition in a dissolved state; and
homogeneous mixing the hydrophobic matrix with the dissolved
pharmaceutically active composition to form the paste-like or
semi-solid drug-delivery composition.
5. The method according to claim 1, wherein the pharmaceutically
active composition comprises at least a pharmaceutically active
compound and at least one excipient selected from the group
consisting of monosaccharides, disaccharides, oligosaccharides,
polysaccharides like hyaluronic acid, pectin, gum arabic and other
gums, albumin, chitosan, collagen, collagen-n-hydroxysuccinimide,
fibrin, fibrinogen, gelatin, globulin, polyaminoacids, polyurethane
comprising amino acids, prolamin, protein-based polymers,
copolymers and derivatives thereof, and mixtures thereof.
6. The method according to claim 1, wherein the pharmaceutically
active composition comprises at least a pharmaceutically active
compound without any excipients.
7. The method according to claim 1, wherein the forming of the
paste-like or semi-solid drug-delivery composition includes
repeated cycles of pressing and folding, in an algorithmic manner,
of the mixture of the hydrophobic matrix and the pharmaceutically
active composition.
8. The method according to claim 4, wherein the dissolved
pharmaceutically active composition is added step-wise during
mixing comprising repeated pressing and folding of the mixture of
the hydrophobic matrix and the pharmaceutically active
composition.
9. The method according to claim 7, wherein the pressing applies a
pressure of not more than 10.sup.6 Nm.sup.-2.
10. The method according to claim 1, wherein the pharmaceutically
active composition is dissolved in an aqueous solution before being
mixed with the hydrophobic matrix.
11. The method according to claim 1, further comprising one of:
simultaneous mixing of at least a hydrophobic solid component, a
hydrophobic liquid component, and the pharmaceutically active
composition dissolved in an aqueous solution to form the paste-like
or semi-solid drug-delivery composition; and mixing of at least a
hydrophobic solid component and a hydrophobic liquid component to
form the hydrophobic matrix, and adding the pharmaceutically active
composition dissolved in an aqueous solution to the hydrophobic
matrix to form the paste-like or semi-solid drug-delivery
composition.
12. The method according to claim 3, wherein the pharmaceutical
active composition powder comprises particles in a size range from
about 100 nm to about 50 .mu.m.
13. The method according to claim 1, wherein the hydrophobic matrix
comprises a solid component and a liquid hydrophobic component,
wherein the solid component is selected from waxes, fruit wax,
carnauba wax, bees wax, waxy alcohols, plant waxes, soybean waxes,
synthetic waxes, triglycerides, lipids, long-chain fatty acids and
their salts like magnesium stearate, magnesium palmitate, esters of
long-chain fatty acids, long-chain alcohols like cetyl palmitate,
waxy alcohols, long-chain alcohols like cetylalcohol, oxethylated
plant oils, oxethylated fatty alcohols, and wherein the liquid
hydrophobic component is selected from plant oils, castor oil,
jojoba oil, soybean oil, silicon oils, paraffin oils, and mineral
oils, cremophor, oxethylated plant oils, oxethylated fatty
alcohols.
14. The method according to claim 1, wherein the pharmaceutically
active composition comprises a pharmaceutically active compound
selected from the group consisting of immunoglobulins, fragments or
fractions of immunoglobulins, synthetic substance mimicking
immunoglobulins or fragments or fractions thereof, proteins
peptides having a molecular mass equal to or higher than 3 kDa,
ribonucleic acids (RNA), desoxyribonucleic acids (DNA) including
aptamers and spiegelmers, plasmids, peptide nucleic acids (PNA),
steroids, and corticosteroids.
15. The method according to claim 1, wherein the pharmaceutically
active composition comprises a pharmaceutically active compound
selected from the group consisting of immunoglobulins, fragments or
fractions of immunoglobulins, synthetic substance mimicking
immunoglobulins or synthetic, semisynthetic or biosynthetic
fragments or fractions thereof, chimeric, humanized or human
monoclonal antibodies, Fab fragments, fusion proteins or receptor
antagonists (e.g., anti TNF alpha, Interleukin-1, Interleukin-6
etc.), antiangiogenic compounds (e.g., anti-VEGF, anti-PDGF etc.),
intracellular signaling inhibitors (e.g JAK1,3 and SYK inhibitors),
peptides having a molecular mass equal to or higher than 3 kDa,
ribonucleic acids (RNA), desoxyribonucleic acids (DNA), plasmids,
peptide nucleic acids (PNA), steroids, corticosteroids, an
adrenocorticostatic, an antibiotic, an antidepressant, an
antimycotic, a [beta]-adrenolytic, an androgen or antiandrogen, an
antianemic, an anabolic, an anaesthetic, an analeptic, an
antiallergic, an antiarrhythmic, an antiarterosclerotic, an
antibiotic, an antifibrinolytic, an anticonvulsive, an
antiinflammatory drug, an anticholinergic, an antihistaminic, an
antihypertensive, an antihypotensive, an anticoagulant, an
antiseptic, an antihemorrhagic, an antimyasthenic, an
antiphlogistic, an antipyretic, a beta-receptor antagonist, a
calcium channel antagonist, a cell, a cell differentiation factor,
a chemokine, a chemotherapeutic, a coenzyme, a cytotoxic agent, a
prodrug of a cytotoxic agent, a cytostatic, an enzyme and its
synthetic or biosynthetic analogue, a glucocorticoid, a growth
factor, a haemostatic, a hormone and its synthetic or biosynthetic
analogue, an immunosuppressant, an immunostimulant, a mitogen, a
physiological or pharmacological inhibitor of mitogens, a
mineralcorticoid, a muscle relaxant, a narcotic, a
neurotransmitter, a precursor of a neurotransmitter, an
oligonucleotide, a peptide, a (para)-sympathicomimetic, a
(para)-sympatholytic, a protein, a sedating agent, a spasmolytic, a
vasoconstrictor, a vasodilatator, a vector, a virus, a virus-like
particle, a virustatic, a wound-healing substance, and combinations
thereof.
16. The method according to claim 1, further comprising: forming
the drug-delivery composition into an applicable form.
17. A drug-delivery composition, comprising: a paste-like or
semi-solid mixture comprising at least a hydrophobic matrix and a
pharmaceutically active compound.
18. The drug-delivery composition according to claim 17, wherein
the pharmaceutically active compound is dispersed in the
hydrophobic matrix in particulate form.
19. The drug-delivery composition according to claim 17, wherein
the pharmaceutically active compound is dispersed in the
hydrophobic matrix in a dissolved state.
20. The drug-delivery composition according to claim 19, wherein
the pharmaceutically active compound is dissolved in a solution
comprising water and electrolytes.
21. The drug-delivery composition according to claim 19, wherein
the pharmaceutically active compound is dissolved in a solution
comprising water, electrolytes and at least one of monosaccharides,
disaccharides, oligosaccharides, polysaccharides like hyaluronic
acid, pectin, gum arabic and other gums, albumin, chitosan,
collagen, collagen-n-hydroxysuccinimide, fibrin, fibrinogen,
gelatin, globulin, polyaminoacids, polyurethane comprising amino
acids, prolamin, protein-based polymers, copolymers and derivatives
thereof, and mixtures thereof.
22. The drug-delivery composition according to claim 17, wherein
the paste-like or semi-solid mixture has a modulus of elasticity at
least of 10.sup.-4Nmm.sup.-2.
23. The drug-delivery composition according to claim 17, wherein
the paste-like or semi-solid mixture has a viscosity of at least
100 mPas.
24. The drug-delivery composition according to claim 17, wherein
the pharmaceutically active compound is selected from the group
consisting of immunoglobulins, fragments or fractions of
immunoglobulins, synthetic substance mimicking immunoglobulins or
fragments or fractions thereof, proteins, peptides having a
molecular mass equal to or higher than 3 kDa, ribonucleic acids
(RNA), desoxyribonucleic acids (DNA), plasmids, peptide nucleic
acids (PNA), aptamers, spiegelmers, steroids, and
corticosteroids.
25. The drug-delivery composition according to claim 17, wherein
the pharmaceutically active compound is selected from the group
consisting of: immunoglobulins, fragments or fractions of
immunoglobulins, synthetic substance mimicking immunoglobulins or
synthetic, semisynthetic or biosynthetic fragments or fractions
thereof, chimeric, humanized or human monoclonal antibodies, Fab
fragments, fusion proteins or receptor antagonists (e.g., anti TNF
alpha, Interleukin-1, Interleukin-6 etc.), antiangiogenic compounds
(e.g., anti-VEGF, anti-PDGF etc.), intracellular signaling
inhibitors (e.g JAK1,3 and SYK inhibitors), peptides having a
molecular mass equal to or higher than 3 kDa, ribonucleic acids
(RNA), desoxyribonucleic acids (DNA), plasmids, peptide nucleic
acids (PNA), steroids, corticosteroids, an adrenocorticostatic, an
antibiotic, an antidepressant, an antimycotic, a
[beta]-adrenolytic, an androgen or antiandrogen, an antianemic, an
anabolic, an anaesthetic, an analeptic, an antiallergic, an
antiarrhythmic, an antiarterosclerotic, an antibiotic, an
antifibrinolytic, an anticonvulsive, an antiinflammatory drug, an
anticholinergic, an antihistaminic, an antihypertensive, an
antihypotensive, an anticoagulant, an antiseptic, an
antihemorrhagic, an antimyasthenic, an antiphlogistic, an
antipyretic, a beta-receptor antagonist, a calcium channel
antagonist, a cell, a cell differentiation factor, a chemokine, a
chemotherapeutic, a coenzyme, a cytotoxic agent, a prodrug of a
cytotoxic agent, a cytostatic, an enzyme and its synthetic or
biosynthetic analogue, a glucocorticoid, a growth factor, a
haemostatic, a hormone and its synthetic or biosynthetic analogue,
an immunosuppressant, an immunostimulant, a mitogen, a
physiological or pharmacological inhibitor of mitogens, a
mineralcorticoid, a muscle relaxant, a narcotic, a
neurotransmitter, a precursor of a neurotransmitter, an
oligonucleotide, a peptide, a (para)-sympathicomimetic, a
(para)-sympatholytic, a protein, a sedating agent, a spasmolytic, a
vasoconstrictor, a vasodilatator, a vector, a virus, a virus-like
particle, a virustatic, a wound-healing substance, and combinations
thereof.
26. The drug-delivery composition according to claim 17, wherein
the hydrophobic matrix comprises at least a hydrophobic solid
component and a hydrophobic liquid component, wherein the mass
ratio of the hydrophobic solid component to the hydrophobic liquid
component is below 2.8:1.
27. The drug-delivery composition according to claim 17, wherein
the mass of the pharmaceutically active compound is up to 25% (w/w)
of the total mass of the paste-like or semi-solid mixture.
28. The drug-delivery composition according to claim 17, wherein
the mass of the pharmaceutically active compound is at least 0.01%
(w/w) of the total mass of the paste-like or semi-solid
mixture.
29. A method for delivery a drug-delivery composition, comprising:
providing a drug-delivery composition comprising a paste-like or
semi-solid mixture comprising at least a hydrophobic matrix and a
pharmaceutically active compound; and applying the drug-delivery
composition into a human or animal body.
30. The method of claim 29, wherein applying the mixture into the
human or animal body comprises at least one of: implanting or
injecting the mixture into a human or animal body; intraocular
injecting the mixture into a human, or animal body; subcutaneous
injecting the mixture into a human, or animal body; intramuscular
injecting the mixture into a human, or animal body; intraperitoneal
injecting the mixture into a human, or animal body; intravenous
injecting the mixture into a human, or animal body; inhalative
administering the mixture into a human, or animal body; and
intranasal administering the mixture into a human, or animal body.
Description
FIELD OF THE INVENTION
[0001] The present invention belongs to the field of controlled
drug release, particularly to methods for manufacturing
drug-delivery compositions including pharmaceutically active
substances or compounds, and to the controlled delivery thereof
into living organisms and tissues for therapeutic purposes.
BACKGROUND OF THE INVENTION
[0002] Most therapeutic dosage forms include mixtures of one or
more active pharmaceutical ingredients (APIs) with additional
components referred to as excipients. APIs are substances that
exert a pharmacological effect on a living tissue or organism,
whether used for prevention, treatment, or cure of a disease. APIs
can be naturally occurring or synthetic substances, or can be
produced by recombinant methods, or any combination of these
approaches.
[0003] Numerous methods have been devised for delivering APIs into
living organisms, each with more or less success. Traditional oral
therapeutic dosage forms include both solids (tablets, capsules,
pills, etc.) and liquids (solutions, suspensions, emulsions, etc.).
Parenteral dosage forms include solids and liquids as well as
aerosols (administered by inhalers, etc.), injectables
(administered with syringes, micro-needle arrays, etc.), topicals
(foams, ointments, etc.), and suppositories, among other dosage
forms. Although these dosage forms might be effective in delivering
low molecular weight APIs, each of these various methods suffers
from one or more drawbacks, including the lack of bioavailability
as well as the inability to completely control either the spatial
or the temporal component of the API's distribution when it comes
to high molecular weight APIs. These drawbacks are especially
challenging for administering biotherapeutics, i.e.
pharmaceutically active peptides (e.g. growth factors), proteins
(e.g. enzymes, antibodies), oligonucleotides and nucleic acids
(e.g. RNA, DNA, PNA, aptamers, spiegelmers), hormones and other
natural substances or synthetic substances mimicking such, since
many types of pharmacologically active biomolecules at least
partially are broken down either in the digestive tract or in the
blood system and are delivered suboptimally to the target site.
[0004] Therefore, an ongoing need exists for improved drug-delivery
methods in the life sciences, including but not limited to human
and veterinary medicine. One important goal for any new
drug-delivery method is to deliver the desired therapeutic agent(s)
to a specific place in the body over a specific and controllable
period of time, i.e. controlling the delivery of one or more
substances to specific organs and tissues in the body in both a
spatial and temporal manner. Methods for accomplishing this
spatially and temporally controlled delivery are known as
controlled-release drug-delivery methods. Delivering APIs to
specific organs and tissues in the body offers several potential
advantages, including increased patient compliance, extending
activity, lowering the required dose, minimizing side effects, and
permitting the use of more potent therapeutics. In some cases,
controlled-release drug-delivery methods can even allow the
administration of therapeutic agents which would otherwise be too
toxic or ineffective for use.
[0005] There are five broad types of solid dosage forms for
controlled-delivery oral administration: reservoir and matrix
diffusive dissolution, osmotic, ion-exchange resins, and prodrugs.
For parenterals, most of the above solid dosage forms are available
as well as injections (intravenous, intramuscular, etc.),
transdermal systems, and implants. Numerous products have been
developed for both oral and parenteral administration, including
depots, pumps, micro- and nano-particles.
[0006] The incorporation of APIs into polymer matrices acting as a
core reservoir is one approach for controlling their delivery.
Contemporary approaches for formulating such drug-delivery systems
are dependent on technological capabilities as well as the specific
requirements of the application. For sustained delivery systems
there a two main structural approaches: the release controlled by
diffusion through a barrier such as shell, coat, or membrane, and
the release controlled by the intrinsic local binding strength of
the API(s) to the core or to other ingredients in the core
reservoir.
[0007] Another strategy for controlled delivery of therapeutic
agents, especially for delivering biotherapeutics, involves their
incorporation into polymeric micro- and nano-particles either by
covalent or cleavable linkage or by trapping or adsorption inside
porous network structures. Various particle architectures can be
obtained, for instance core/shell structures. Typically one or more
APIs are contained either in the core, in the shell, or in both
components. Their concentration can be different throughout the
respective component in order to modify the release pattern.
Although polymeric nano-spheres can be effective in the controlled
delivery of APIs, they also suffer from several disadvantages. For
example, their small size can allow them to diffuse in and out of
the target tissue or being successfully attacked by macrophages.
The use of intravenous nano-particles may also be limited due to
rapid clearance by the reticuloendothelial system. Notwithstanding
this, polymeric micro-spheres remain an important delivery
vehicle.
[0008] In view of the above, there is a need for improving
drug-delivery methods and compositions.
SUMMARY OF THE INVENTION
[0009] According to an embodiment, a method for manufacturing a
drug-delivery composition is provided. The method includes
providing at least a pharmaceutically active composition, including
a hydrophobic matrix, and a liquid; and mixing the hydrophobic
matrix and the pharmaceutically active composition to form a
paste-like or semi-solid drug-delivery composition.
[0010] According to an embodiment, a drug-delivery composition is
provided, which comprises a paste-like or semi-solid mixture
including at least a hydrophobic matrix and a pharmaceutically
active compound.
[0011] According to an embodiment, a method for delivery a
drug-delivery composition is provided. The method includes
providing a drug-delivery composition including a paste-like or
semi-solid mixture comprising at least a hydrophobic matrix and a
pharmaceutically active compound; and applying the drug-delivery
composition into a human or animal body.
[0012] Those skilled in the art will recognize additional features
and advantages upon reading the following detailed description, and
upon viewing the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] The accompanying drawings are included to further an
understanding of the embodiments that are incorporated in and
constitute a part of this specification. The drawings illustrate
embodiments and together with the description serve to explain
principles of embodiments. Other embodiments and many of the
intended advantages of embodiments will be readily appreciated, as
they become better understood by reference to the following
detailed description. The elements of the drawings are not
necessarily to scale relative to each other.
[0014] FIG. 1 illustrates release of antibodies from hydrophobic
matrices at room temperature.
[0015] FIG. 2 illustrates release of antibody 2 from a hydrophobic
matrix at body temperature.
[0016] FIG. 3 shows a comparison between the mechanically treated
antibody 3 releasing hydrophobic matrix and self-organized antibody
3--releasing hydrophobic matrix.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The following language and descriptions of certain preferred
embodiments of the present invention are provided in order to
further an understanding of the principles of the present
invention. However, it will be understood that no limitations of
the present invention are intended, and that further alterations,
modifications, and applications of the principles of the present
invention are also included.
[0018] For the purpose of this specification, the term "mixing"
intends to describe a mechanical process or a mechanical treatment
of the components. For example, mixing can be in the sense of
carrying out repeated cycles of pressing and folding or comparable
processing steps which lead to an intense compression and mixing of
the provided hydrophobic matrices. The pharmaceutically active
components are referred to hereinafter as active pharmaceutical
ingredients (APIs).
[0019] According to an embodiment a drug-delivery composition is
manufactured by providing at least a pharmaceutically active
composition or API; providing a hydrophobic matrix; and mixing the
hydrophobic matrix and the pharmaceutically active composition to
form a paste-like or semi-solid drug delivery composition. An
advantage of such a manufacturing method consists in achieving a
sustained release formulation for pharmaceutically active
ingredients with improved release characteristics. In particular,
the method allows preparing drug-delivery compositions for
sustained release of ingredients characterized by a specific
biological activity which otherwise might decrease or even
terminate.
[0020] According to an embodiment a drug-delivery composition is
manufactured, wherein providing the hydrophobic matrix comprises
mixing at least a hydrophobic solid component and a hydrophobic
liquid component. Advantageously by mixing a given liquid
hydrophobic component with a given solid hydrophobic component,
allows preparing a wide range of consistencies i.e. rheological
properties like viscosities of the paste-like or semi-solid
composition depending on their quantitative relation. On the other
hand, by carefully selecting a solid hydrophobic component and a
liquid hydrophobic component, similar consistencies i.e.
rheological properties, like viscosities of the paste-like or
semi-solid composition can be achieved. Furthermore, depending on
the type and quantity of the selected APIs, different hydrophobic
components can be combined in order to form a paste-like or
semi-solid composition with the desired properties.
[0021] According to an embodiment a drug delivery composition is
manufactured, wherein the pharmaceutically active composition is
provided as dry pharmaceutically active powder. Therein, the
hydrophobic matrix is homogeneously mixed with the dry
pharmaceutically active composition powder to form a paste-like or
semi-solid drug-delivery composition. That allows arriving at a
drug-delivery composition with the pharmaceutically active
composition being homogeneously distributed within the hydrophobic
matrix. Such drug-delivery compositions allow delivering the API
over prolonged time periods.
[0022] According to an embodiment a drug delivery composition is
manufactured, wherein the pharmaceutically active composition
powder comprises particles in a size range from about 100 nm to
about 50 .mu.m. Such particle sizes are provided applying, e.g.
lyophilized proteins.
[0023] According to an embodiment a drug delivery composition is
manufactured, wherein the pharmaceutically active composition is
provided in a solved state. It is homogeneously mixed with the
hydrophobic matrix to form a paste-like or semi-solid drug-delivery
composition. Advantageously, at least a solid hydrophobic substance
and a liquid hydrophobic substance are mixed simultaneously with
the dissolved API to form a paste-like or semi-solid drug-delivery
composition. Optionally, the dissolved APIs can be added to the
already premixed hydrophobic substances to form the paste-like or
semi-solid drug-delivery composition.
[0024] According to an embodiment the drug-delivery composition is
manufactured as described above, wherein the pharmaceutically
active composition comprises at least the pharmaceutically active
compound and at least one excipient selected from the group
consisting of monosaccharides, disaccharides, oligosaccharides,
polysaccharides like hyaluronic acid, pectin, gum arabic and other
gums, albumin, chitosan, collagen, collagen-n-hydroxysuccinimide,
fibrin, fibrinogen, gelatin, globulin, polyaminoacids, polyurethane
comprising amino acids, prolamin, protein-based polymers,
copolymers and derivatives thereof, and mixtures thereof. An
advantage thereof consists in further modifying release
characteristics of the drug-delivery paste-like or semi-solid
composition.
[0025] According to an embodiment a drug delivery composition is
manufactured, wherein the dissolved pharmaceutically active
composition comprises at least a pharmaceutically active compound
without any excipients.
[0026] According to an embodiment a drug-delivery paste-like or
semi-solid composition is manufactured, wherein the forming of the
paste-like or semi-solid drug-delivery composition includes
repeated cycles of pressing and folding, e.g. pressing and folding
in an algorithmic manner of the hydrophobic matrix itself and/or
mixed with the pharmaceutically active composition.
[0027] According to an embodiment, no heating to transfer the
hydrophobic solid component into a liquid state is used. In
particular the solid hydrophobic matrix is kept throughout the
mechanical treatment in a non-molten state.
[0028] According to an embodiment, active cooling is used in order
to keep the hydrophobic matrix in a non-molten state throughout the
pressing and folding cycles. This approach prevents
self-organization processes to occur.
[0029] According to an embodiment the temperature of the mixture
during pressing and folding cycles can be kept below a certain
temperature value by cooling. Advantageously, that allows
protecting susceptible biologically active substances such as
proteins from denaturation, for instance by keeping the temperature
of the mixture below 37.degree. C., below 45.degree. C., below
50.degree. C., or especially below 60.degree. C.
[0030] According to an embodiment the paste-like or semi-solid
drug-delivery composition is manufactured by step-wise adding the
dissolved APIs during repeated pressing and folding of the mixture
of the hydrophobic substances forming the hydrophobic matrix. It is
an advantage of that particular embodiment that the APIs can be
distributed within the hydrophobic matrix homogeneously applying
that process.
[0031] According to an embodiment of the manufacturing process
pressures of not more than 10.sup.6 Nm.sup.-2 are applied during
the described pressing and folding cycles.
[0032] According to an embodiment a drug-delivery paste-like or
semi-solid composition is manufactured using APIs in dissolved
state, wherein the pharmaceutically active composition is dissolved
in an aqueous solution before being mixed with the hydrophobic
matrix.
[0033] According to an embodiment the paste-like or semi-solid
drug-delivery composition is manufactured from APIs and hydrophobic
components, wherein the pharmaceutically active composition is
dissolved in an aqueous solution and is either simultaneously mixed
with at least a hydrophobic solid component and a hydrophobic
liquid component to form a paste-like or semi-solid drug-delivery
composition; or the pharmaceutically active composition dissolved
in an aqueous solution is added after the mixing of at least a
hydrophobic solid component and at least a hydrophobic liquid
component.
[0034] According to an embodiment the paste-like or semi-solid
drug-delivery composition is manufactured from API(s) and
hydrophobic components, wherein the hydrophobic matrix comprises a
solid component and a liquid hydrophobic component. Therein the
solid component is selected from waxes, fruit wax, carnauba wax,
bees wax, waxy alcohols, plant waxes, soybean waxes, synthetic
waxes, triglycerides, lipids, long-chain fatty acids and their
salts like magnesium stearate, magnesium palmitate, esters of
long-chain fatty acids, long-chain alcohols like cetyl palmitate,
waxy alcohols, long-chain alcohols like cetylalcohol, oxethylated
plant oils, oxethylated fatty alcohols.
[0035] According to an embodiment the pharmaceutically active
composition for preparing the paste-like or semi-solid
drug-delivery composition is selected from the group consisting of:
immunoglobulins, fragments or fractions of immunoglobulins,
synthetic substance mimicking immunoglobulins or fragments or
fractions thereof, proteins, peptides having a molecular mass equal
to or higher than 3.000 Dalton, ribonucleic acids (RNA),
desoxyribonucleic acids (DNA), aptamers, spiegelmers, plasmids,
peptide nucleic acids (PNA), steroids, and corticosteroids, and
combinations thereof.
[0036] According to an embodiment, the pharmaceutically active
compound can be one or more of immunoglobulins, fragments or
fractions of immunoglobulins, synthetic substance mimicking
immunoglobulins or synthetic, semisynthetic or biosynthetic
fragments or fractions thereof, chimeric, humanized or human
monoclonal antibodies, Fab fragments, fusion proteins or receptor
antagonists (e.g., anti TNF alpha, Interleukin-1, Interleukin-6
etc.), antiangiogenic compounds (e.g., anti-VEGF, anti-PDGF etc.),
intracellular signaling inhibitors (e.g JAK1,3 and SYK inhibitors),
peptides having a molecular mass equal to or higher than 3 kDa,
ribonucleic acids (RNA), desoxyribonucleic acids (DNA), plasmids,
peptide nucleic acids (PNA), steroids, corticosteroids, an
adrenocorticostatic, an antibiotic, an antidepressant, an
antimycotic, a [beta]-adrenolytic, an androgen or antiandrogen, an
antianemic, an anabolic, an anaesthetic, an analeptic, an
antiallergic, an antiarrhythmic, an antiarterosclerotic, an
antibiotic, an antifibrinolytic, an anticonvulsive, an
antiinflammatory drug, an anticholinergic, an antihistaminic, an
antihypertensive, an antihypotensive, an anticoagulant, an
antiseptic, an antihemorrhagic, an antimyasthenic, an
antiphlogistic, an antipyretic, a beta-receptor antagonist, a
calcium channel antagonist, a cell, a cell differentiation factor,
a chemokine, a chemotherapeutic, a coenzyme, a cytotoxic agent, a
prodrug of a cytotoxic agent, a cytostatic, an enzyme and its
synthetic or biosynthetic analogue, a glucocorticoid, a growth
factor, a haemostatic, a hormone and its synthetic or biosynthetic
analogue, an immunosuppressant, an immunostimulant, a mitogen, a
physiological or pharmacological inhibitor of mitogens, a
mineralcorticoid, a muscle relaxant, a narcotic, a
neurotransmitter, a precursor of a neurotransmitter, an
oligonucleotide, a peptide, a (para)-sympathicomimetic, a
(para)-sympatholytic, a protein, a sedating agent, a spasmolytic, a
vasoconstrictor, a vasodilatator, a vector, a virus, a virus-like
particle, a virustatic, a wound-healing substance, and combinations
thereof.
[0037] According to an embodiment a drug delivery composition is
manufactured as described above, further comprising forming the
drug-delivery composition into an applicable form. In particular,
the resulting hydrophobic drug-delivery body can be transferred
into the final dosage form, i.e. into bodies or micro-particles of
desired shape, size and size distribution by means of colloid
forming techniques and other technological procedures. Colloid
forming techniques comprise e.g. milling, cold extruding,
emulgating, dispersing, sonificating. The compositions formed by
the methods described herein maintain the drug-releasing properties
for a prolonged time such as weeks and months. The APIs remain
protected in the paste-like or semi-solid mixture so that their
specific biological activity can be maintained. If desired,
additional barrier layers can be formed around the paste-like or
semi-solid mixture.
[0038] According to an embodiment, a micro-porous membrane made
from ethylene/vinyl acetate copolymer or other materials for ocular
use can be formed around the paste-like or semi-solid mixture.
Further options include use of biodegradable polymers for
subcutaneous and intramuscular injection, bioerodible
polysaccharides, hydrogels etc.
[0039] According to an embodiment a drug-delivery composition is
provided, comprising a paste-like or semi-solid mixture comprising
at least a hydrophobic matrix and a pharmaceutically active
compound.
[0040] According to an embodiment a drug-delivery composition is
provided, wherein the pharmaceutically active compound is dispersed
in the hydrophobic matrix in particulate form.
[0041] According to an embodiment a drug-delivery composition is
provided, wherein the pharmaceutically active compound is dispersed
in the hydrophobic matrix in a dissolved state.
[0042] According to an embodiment a drug-delivery composition is
provided, wherein the pharmaceutically active compound is dissolved
in a solution comprising water and electrolytes.
[0043] According to an embodiment a drug-delivery composition is
provided, wherein the pharmaceutically active compound is dissolved
in a solution comprising water, electrolytes and at least one of
monosaccharides, disaccharides, oligosaccharides, polysaccharides
like hyaluronic acid, pectin, gum arabic and other gums, albumin,
chitosan, collagen, collagen-n-hydroxysuccinimide, fibrin,
fibrinogen, gelatin, globulin, polyaminoacids, polyurethane
comprising amino acids, prolamin, protein-based polymers,
copolymers and derivatives thereof, and mixtures thereof.
[0044] According to an embodiment a drug-delivery composition is
provided, wherein the paste-like or semi-solid mixture has a
modulus of elasticity at least of 10.sup.-4Nmm.sup.-2.
[0045] According to an embodiment a drug-delivery composition is
provided, wherein the paste-like or semi-solid mixture has a
viscosity of at least 100 mPas.
[0046] According to an embodiment a drug-delivery composition is
provided, wherein the pharmaceutically active compound is selected
from the group consisting of immunoglobulins, fragments or
fractions of immunoglobulins, synthetic substances mimicking
immunoglobulins or fragments or fractions thereof, therapeutic
proteins, peptides having a molecular mass equal to or higher than
3 kDa, ribonucleic acids (RNA), desoxyribonucleic acids (DNA),
plasmids, peptide nucleic acids (PNA), aptamers, spiegelmers,
steroids, and corticosteroids, and combinations thereof.
[0047] According to an embodiment a drug-delivery composition is
provided, wherein the pharmaceutically active compound is selected
from the group consisting of: immunoglobulins, fragments or
fractions of immunoglobulins, synthetic substance mimicking
immunoglobulins or synthetic, semisynthetic or biosynthetic
fragments or fractions thereof, chimeric, humanized or human
monoclonal antibodies, Fab fragments, fusion proteins or receptor
antagonists (e.g., anti TNF alpha, Interleukin-1, Interleukin-6
etc.), antiangiogenic compounds (e.g., anti-VEGF, anti-PDGF etc.),
intracellular signaling inhibitors (e.g JAK1,3 and SYK inhibitors),
peptides having a molecular mass equal to or higher than 3 kDa,
ribonucleic acids (RNA), desoxyribonucleic acids (DNA), plasmids,
peptide nucleic acids (PNA), steroids, corticosteroids, an
adrenocorticostatic, an antibiotic, an antidepressant, an
antimycotic, a [beta]-adrenolytic, an androgen or antiandrogen, an
antianemic, an anabolic, an anaesthetic, an analeptic, an
antiallergic, an antiarrhythmic, an antiarterosclerotic, an
antibiotic, an antifibrinolytic, an anticonvulsive, an
antiinflammatory drug, an anticholinergic, an antihistaminic, an
antihypertensive, an antihypotensive, an anticoagulant, an
antiseptic, an antihemorrhagic, an antimyasthenic, an
antiphlogistic, an antipyretic, a beta-receptor antagonist, a
calcium channel antagonist, a cell, a cell differentiation factor,
a chemokine, a chemotherapeutic, a coenzyme, a cytotoxic agent, a
prodrug of a cytotoxic agent, a cytostatic, an enzyme and its
synthetic or biosynthetic analogue, a glucocorticoid, a growth
factor, a haemostatic, a hormone and its synthetic or biosynthetic
analogue, an immunosuppressant, an immunostimulant, a mitogen, a
physiological or pharmacological inhibitor of mitogens, a
mineralcorticoid, a muscle relaxant, a narcotic, a
neurotransmitter, a precursor of a neurotransmitter, an
oligonucleotide, a peptide, a (para)-sympathicomimetic, a
(para)-sympatholytic, a protein, a sedating agent, a spasmolytic, a
vasoconstrictor, a vasodilatator, a vector, a virus, a virus-like
particle, a virustatic, a wound-healing substance, and combinations
thereof.
[0048] According to an embodiment a drug-delivery composition is
provided, wherein the hydrophobic matrix comprises at least a
hydrophobic solid component and a hydrophobic liquid component,
wherein the mass ratio of the hydrophobic solid component to the
hydrophobic liquid component is below 2.8:1.
[0049] According to an embodiment a drug-delivery composition is
provided, wherein the mass of the pharmaceutically active compound
is up to 25% (w/w) of the total mass of the paste-like or
semi-solid mixture.
[0050] According to an embodiment a drug-delivery composition is
provided, wherein the mass of the pharmaceutically active compound
is at least 0.1% (w/w) of the total mass of the paste-like or
semi-solid mixture.
[0051] According to an embodiment a method for delivery a
drug-delivery composition is suggested, comprising: providing a
drug-delivery composition comprising a paste-like or semi-solid
mixture comprising at least a hydrophobic matrix and a
pharmaceutically active compound; and applying the drug-delivery
composition into a human or animal body.
[0052] According to an embodiment a method for delivery a
drug-delivery composition is suggested, wherein applying the
mixture into the human or animal body comprises at least one of:
implanting or injecting the mixture into a human or animal body;
intraocular injecting the mixture into a human, or animal body;
subcutaneous injecting the mixture into a human, or animal body;
intramuscular injecting the mixture into a human, or animal body;
and intraperitoneal injecting the mixture into a human, or animal
body, intravenous injecting the mixture into a human, or animal
body; inhalative or intranasal administration of the mixture into
the human or animal body.
[0053] According to typical embodiments the described treatment of
the hydrophobic matrices comprises intimate mixing a solid
hydrophobic material and a liquid hydrophobic material with APIs to
achieve an API-containing semi-solid material possessing superior
controlled-delivery properties. According to an embodiment the
API(s) are added to already treated hydrophobic matrices or at a
late stage of their treatment, i.e their intimate mixing.
[0054] Surprisingly, the mechanical treatment comprising repeated
pressing and folding cycles is slowing down the release kinetics
and making the release of the API more sustained.
[0055] The suggested method of algorithmic processes of pressing
and folding is especially suitable for formulating biologically
active compounds. Biopolymers like proteins, peptides, poly- and
oligonucleotides are particularly sensitive to changes in their
environment and may lose their specific activity more readily than
small-molecule APIs. Synthetic APIs and excipients mimicking
biomacromolecules may carry both anionic and cationic groups in the
relevant medium or may possess different functional groups in
variable density on a molecular backbone.
[0056] The suggested approach combines the benefit of initial
thorough mixing of the hydrophobic matrix with the
controlled-release of microparticles but does not suffer from the
disadvantages of any of these formulations when applied alone.
[0057] The matrix formed by the mechanical treatment of solid and
liquid components is typically a hydrophobic matrix but can also
include a small amount of hydrophilic excipients/ingredients.
[0058] The suggested method is different from other approaches in
that the paste-like or semi-solid composition is formed by
mechanical treatment, i.e. repeated pressing and folding cycles.
Particularly, according to an embodiment, the paste-like or
semi-solid composition is formed by kneading which is an example of
an algorithmic pressing-folding cycle.
[0059] According to an embodiment, the pharmaceutically active
substance or API is provided as dry pharmaceutically active
compound powder. The solid and liquid hydrophobic components are
homogeneously mixed with each other with or without the presence of
the dry pharmaceutically active compound to prepare a sustained
delivery body.
[0060] The mechanical procedures can include repeatedly pressing
and folding the mixture of the hydrophobic solid and liquid
materials. The mechanical procedures may start with pressing to
bring the mass into a more flat shape and then folding the mass,
for example by a blade or other suitable means. The folded mass is
then pressed again. By repeating these processes a better
distribution of the pharmaceutically active compound (API)
throughout the matrix can be achieved.
[0061] The API(s) can be added to the treated system during all
phases of the preparation process, and, according to an embodiment,
at a late stage after forming an established excipient matrix
system. The late addition of the APIs to the already homogenized
mixture of hydrophobic constituents minimizes the influence of
mechanical mixing on the APIs.
[0062] According to an embodiment, the mechanical processing of the
mass can also include other processes such as rolling, extrusion
from or through a nip between rolls.
[0063] The force acting on the mass may be limited to avoid
excessive mechanical impact, which might affect the API. According
to an embodiment, a pressure of not more than 10.sup.6 Nm.sup.-2 is
applied to the mass. According to further embodiments, a pressure
of not more than 5.times.10.sup.5Nm.sup.-2 is applied to the
mass.
[0064] According to an embodiment, the mechanical treatment of the
hydrophobic matrix components yields a homogeneous distribution of
the API within the matrix.
[0065] The APIs may be provided as dry component or the APIs may be
dissolved in an aqueous solution.
[0066] According to an embodiment, the APIs can be provided in
particulate form such as micro- or nano-particles. Suitable
particle sizes range from about 100 nm to about 50 .mu.m,
particularly from about 500 nm to about 30 .mu.m, and more
particularly from about 1 .mu.m to about 10 .mu.m.
[0067] In the approach described herein, the controlled mixing of
the components into a homogeneous mass transforms the preparation
into a paste- or dough-like consistency, which is appropriate for
the production of slow release compositions. The processes
according to one embodiment include mixing of all solid hydrophobic
ingredients in a first step followed by adding the liquid
hydrophobic matrix component to generate the paste-like or
semi-solid consistency during mechanical treatment. The APIs is
added, for instance as a dry powder into the paste like mass and
the mechanical treatment is continued to gain homogeneity of the
paste like mass.
[0068] According to an embodiment, APIs can be small molecules,
peptides, proteins, therapeutic proteins, antibodies, antigens,
enzymes, receptor ligands, nucleotides or nucleotide analogs,
oligonucleotides and oligonucleotide analogs (aptamers and
spiegelmers), genes or gene-like species, viruses, virus-like
particles, sugars or polysaccharides or their analogs, or any other
physical composition such as living organelles, cells, or tissue
constituents.
[0069] According to an embodiment excipients can include almost any
member of these same classes of species. They often act as buffer,
filler, binder, osmotic agent, lubricant, or fulfill similar
functions. Polyampholytes are multiply-charged polymers, which bear
both anionic and cationic groups in the relevant medium, e.g. in an
aqueous solution. The various classes and types of APIs,
excipients, polymers, and polyampholytes are familiar to those
skilled in the art of drug delivery.
[0070] According to an embodiment, an example for an excipient can
be a sugar selected from monosaccharides, disaccharides,
oligosaccharides, polysaccharides. The excipients can further
comprise albumin, chitosan, collagen,
collagen-n-hydroxysuccinimide, fibrin, fibrinogen, gelatin,
globulin, polyaminoacids, polyurethane comprising amino acids,
prolamin, protein-based polymers, copolymers and derivatives
thereof, and mixtures thereof.
[0071] According to an embodiment, the pharmaceutically active
compound can be one or more of immunoglobulins, fragments or
fractions of immunoglobulins, synthetic substance mimicking
immunoglobulins or synthetic, semisynthetic or biosynthetic
fragments or fractions thereof, chimeric, humanized or human
monoclonal antibodies, Fab fragments, fusion proteins or receptor
antagonists (e.g., anti TNF alpha, Interleukin-1, Interleukin-6
etc.), antiangiogenic compounds (e.g., anti-VEGF, anti-PDGF etc.),
intracellular signaling inhibitors (e.g JAK1,3 and SYK inhibitors),
peptides having a molecular mass equal to or higher than 3 kDa,
ribonucleic acids (RNA), desoxyribonucleic acids (DNA), plasmids,
peptide nucleic acids (PNA), steroids, corticosteroids, an
adrenocorticostatic, an antibiotic, an antidepressant, an
antimycotic, a [beta]-adrenolytic, an androgen or antiandrogen, an
antianemic, an anabolic, an anaesthetic, an analeptic, an
antiallergic, an antiarrhythmic, an antiarterosclerotic, an
antibiotic, an antifibrinolytic, an anticonvulsive, an
antiinflammatory drug, an anticholinergic, an antihistaminic, an
antihypertensive, an antihypotensive, an anticoagulant, an
antiseptic, an antihemorrhagic, an antimyasthenic, an
antiphlogistic, an antipyretic, a beta-receptor antagonist, a
calcium channel antagonist, a cell, a cell differentiation factor,
a chemokine, a chemotherapeutic, a coenzyme, a cytotoxic agent, a
prodrug of a cytotoxic agent, a cytostatic, an enzyme and its
synthetic or biosynthetic analogue, a glucocorticoid, a growth
factor, a haemostatic, a hormone and its synthetic or biosynthetic
analogue, an immunosuppressant, an immunostimulant, a mitogen, a
physiological or pharmacological inhibitor of mitogens, a
mineralcorticoid, a muscle relaxant, a narcotic, a
neurotransmitter, a precursor of a neurotransmitter, an
oligonucleotide, a peptide, a (para)-sympathicomimetic, a
(para)-sympatholytic, a protein, a sedating agent, a spasmolytic, a
vasoconstrictor, a vasodilatator, a vector, a virus, a virus-like
particle, a virustatic, a wound-healing substance, and combinations
thereof.
[0072] According to an embodiment, the drug-delivery composition
can be brought into an implantable form to form an implantable
drug-delivery formulation with controlled-release kinetics.
According to the novel proposed approach the hydrophobic matrix
itself can be comprised of natural waxes, fats and oils as well as
synthetic substances or chemically modified natural waxes, fats and
oils. The implantable drug-delivery formulation can be
activated.
[0073] The present invention encompasses not only the use of pure
hydrophobic matrix materials but can comprise also minor amounts of
aqueous solutions. The method and composition described herein can
use any substance which can exert a therapeutic effect, including
small molecules, synthetic or biological macromolecules such as
peptides, proteins, nucleic acids, oligonucleotides, carbohydrates,
and others familiar to one skilled in the art.
[0074] The hydrophobic materials of the present invention can
optionally be labeled with any of a wide variety of agents, which
are known to those skilled in the art. As examples, dyes,
fluorophores, chemiluminescent agents, isotopes, metal atoms or
clusters, radionuclides, enzymes, antibodies, or tight-binding
partners such as biotin and avidin can all be used to label the
hydrophobic drug-delivery composition for detection, localization,
imaging, or any other analytical or medical purpose. The
hydrophobic delivery composition, particularly a liquid component
of the matrix, can also optionally be conjugated with a wide
variety of molecules in order to modify its function, modify its
stability, or further modify the rate of release of the APIs. As
examples, the drug-delivery composition can be coated with a
covalently- or non-covalently-attached layer of a species such as
small molecules, hormones, peptides, proteins, phospholipids,
polysaccharides, mucins, or biocompatible polymers such
polyethylene glycol (PEG), dextran, or any of a number of
comparable materials. The wide range of materials, which can be
used in this fashion, and the methods for accomplishing these
processes, are well known to those skilled in the art.
[0075] The various starting components such as the hydrophobic
matrix and the APIs can be further manipulated and processed using
a wide variety of methods, processes, and equipment familiar to one
skilled in the art. For example, the hydrophobic matrix components
can be thoroughly mixed using any of a number of known methods and
equipment, such as trituration with a mortar and pestle or blending
in a Patterson-Kelley twin-shell blender, before adding the API.
Furthermore, a wide variety of shapes, sizes, morphologies, and
surface compositions of the drug-delivery composition can be
formed. For example, micro-particles or cylindrical bodies with
different aspect ratios can be prepared by means of mechanical
milling, molding, and extruding or similar processes of the
paste-like or semi-solid or even semi-solid material. The resulting
particles can be further treated to prepare them for specific
applications such as e.g. drug delivery systems. As another
example, transforming the mixture, paste or mass into
micro-particles or bodies by means of cold extrusion, cooled
pressure homogenization, molding, and/or other such
well-established procedures can yield a wide range of final
products. As another example, the polymeric drug-delivery
composition can be squeezed through a sieving disk (i.e. a die)
containing predefined pores or channels with uniform pore geometry
and diameter by an extrusion process.
[0076] According to an embodiment, the paste-like or semi-solid
mixture drug-delivery composition has a modulus of elasticity of at
least 10.sup.-4 Nmm.sup.-2. According to an embodiment, the
paste-like or semi-solid mixture drug-delivery composition has a
modulus of elasticity of at least 10.sup.-3 Nmm.sup.2, and
particularly 10.sup.-2 Nmm.sup.-2, and more particularly 10.sup.-1
Nmm.sup.-2.
[0077] According to an embodiment, the paste-like or semi-solid
mixtures has a viscosity of not more than 500 Pas, and particularly
of not more than 250 Pas. According to an embodiment, the
paste-like or semi-solid mixtures has a viscosity of not less than
few mPas, for example 100 mPas, and particularly of not less than 1
Pas.
[0078] According to an embodiment, the pharmaceutical active
compound is provided as powder having particles in a range from
about 100 nm to about 50 .mu.m, particularly from about 500 nm to
about 30 .mu.m, and more particularly from about 1 .mu.m to about
10 .mu.m
[0079] Specific examples are described below. The "UV 280 nm
method" mentioned therein comprises the detection of proteins by
their absorption at 280 nm in physiologically isotonic salt
solution (PBS) against a blank using an UV/VIS spectrophotometer
and quartz cuvettes and using calibrations for different APIs and
different concentrations.
Example 1
[0080] 72 mg of an antibody 2 (of gamma globulin type) solution (25
mg/ml) was added to 170 mg of cetyl alcohol and 50 mg of castor
oil. This mixture was mechanically treated and mixed using an agate
mortar and pestle for 7 minutes. Finally, a spherical particle was
formed by hand and added to 3.3 g of an isotonic sodium chloride
solution containing 0.01% of sodium azide. The release of antibody
1 was determined spectroscopically by the UV 280 nm method under
no-sink conditions (see FIG. 1, sample 1).
Example 2
[0081] 72 mg of a lyophilized antibody 3 (of gamma globulin type)
was added to 90 mg of cetyl alcohol and 50 mg of castor oil. This
mixture was mechanically treated and mixed using an agate mortar
and pestle for 5 minutes. Finally, a spherical particle was formed
by hand and added to 10 g of an isotonic sodium chloride solution
containing 0.01% of sodium azide. The release of antibody 3 was
determined spectroscopically by the UV 280 nm method under no-sink
conditions (see FIG. 1, sample 2).
Example 3
[0082] 100 mg of a solution of antibody 1 (of gamma globulin type)
(50 mg/ml) was added to 95 mg of cetyl alcohol and 75 mg of castor
oil. This mixture was mechanically treated and mixed using an agate
mortar and pestle for 7 minutes. Finally, a spherical particle was
formed by hand and added to 6.4 g of an isotonic sodium chloride
solution containing 0.01% of sodium azide. The release of antibody
2 was determined spectroscopically by the UV 280 nm method under
no-sink conditions. The biological activity of the last measured
concentration value was measured by ELISA as given in brackets (see
FIG. 1, sample 3).
Example 4
[0083] 76 mg of an antibody solution antibody 2 (of gamma globulin
type) (25 mg/ml) was added to 170 mg of cetyl alcohol and 45 mg of
soybean oil. This mixture was mechanically treated using an agate
mortar and pestle for 6 minutes. Finally, a spherical particle was
formed by hand and added to 3.3 g of a phosphate buffered solution
containing 0.01% of sodium azide. The release of antibody 1 was
determined spectroscopically by the UV 280 nm method under sink
conditions. The biological activity of the last measured
concentration value was measured by ELISA as given in brackets (see
FIG. 1, sample 4).
Example 5
[0084] 101 mg of an antibody solution antibody 1 (of gamma globulin
type) (25 mg/ml) was added to 101 mg of cetyl alcohol and 80 mg of
soybean oil. This mixture was mechanically treated using an agate
mortar and pestle for 7 minutes. Finally, a spherical particle was
formed by hand and added to 5.7 g of a phosphate buffered solution
containing 0.01% of sodium azide. The release of antibody 2 was
determined spectroscopically by the UV 280 nm method under sink
conditions. The biological activity of the last measured
concentration value was measured by ELISA as given in brackets (see
FIG. 1, sample 5).
Example 6
[0085] 116 mg of an antibody solution antibody 2 (of gamma globulin
type) (25 mg/ml) was added to 170 mg of magnesium stearate and 78
mg of soybean oil. This mixture was mechanically treated using an
agate mortar and pestle for 7 minutes. Finally, a spherical
particle was formed by hand and added to 5.7 g of a phosphate
buffered solution containing 0.01% of sodium azide. The release of
antibody 1 was determined spectroscopically by the UV 280 nm method
under sink conditions. The biological activity of the last measured
concentration value was measured by ELISA as given in brackets (see
FIG. 1, sample 6).
Example 7
[0086] 98 mg of an antibody solution antibody 1 (of gamma globulin
type) (50 mg/ml) was added to 97 mg of magnesium stearate and 79 mg
of soybean oil. This mixture was mechanically treated using an
agate mortar and pestle for 7 minutes. Finally, a spherical
particle was formed by hand and added to 4.2 g of a phosphate
buffered solution containing 0.01% of sodium azide. The sample was
stored at 37.degree. C. for the experimental period. The release of
antibody was determined spectroscopically by the UV 280 nm method
under sink conditions. The biological activity of the last measured
concentration value was measured by ELISA as indicated in brackets
(see FIG. 2).
[0087] The difference between mechanically treated drug delivery
matrices and the self-organized ones have been studied in example 8
below and is illustrated in FIG. 3.
Example 8
Self Organization
[0088] 13 mg of a lyophilized antibody 3 (of gamma globulin type)
was added to 93 mg of cetyl palmitate and 48 mg of castor oil. This
mixture was homogenized by heating under stirring using a water
bath and a magnetic stirrer to form a molten mass (45.degree. C.).
After cooling down the obtained solid mass was added to 3.0 g of a
phosphate buffered solution containing 0.1% of sodium azide. The
release of antibody 3 was determined spectroscopically by the UV
280 nm method under sink conditions (see FIG. 3, sample 8).
Example 9
Mechanical Treatment
[0089] 11 mg of a lyophilized antibody 3 (of gamma globulin type)
was added to 83 mg of cetyl palmitate and 38 mg of castor oil. This
mixture was mechanically treated and mixed using an agate mortar
and pestle for 7 minutes. Finally, a spherical particle was formed
by kneading for 1 minute and added to 3.0 g of a phosphate buffered
solution containing 0.1% of sodium azide. The release of antibody 3
was determined spectroscopically by the UV 280 nm method under sink
conditions (see FIG. 3, sample 9).
* * * * *