U.S. patent application number 14/960302 was filed with the patent office on 2016-07-07 for injectable, non-aqueous suspension with high concentration of therapeutic agent.
This patent application is currently assigned to Durect Corporation. The applicant listed for this patent is Durect Corporation. Invention is credited to Guohua Chen, Paul R. Houston, Andrew Luk.
Application Number | 20160193346 14/960302 |
Document ID | / |
Family ID | 39564057 |
Filed Date | 2016-07-07 |
United States Patent
Application |
20160193346 |
Kind Code |
A1 |
Houston; Paul R. ; et
al. |
July 7, 2016 |
Injectable, Non-Aqueous Suspension with High Concentration of
Therapeutic Agent
Abstract
An injectable, nonaqueous suspension including at least one
therapeutic agent suspended in a single component vehicle. The
single component vehicle is a single amphiphilic material, such as
a polyethoxylated castor oil or derivative thereof a
polyoxyethylene alkyl ether, a polyoxyethylene sorbitan fatty acid
ester, a polyoxyethylene stearate, a block copolymer of
polyethylene oxide-polypropylene oxide-polyethylene oxide, a block
copolymer of polypropylene oxide-polyethylene oxide-polypropylene
oxide, a tetra-functional block copolymer of polyethylene
oxide-polypropylene oxide, or a tetra-functional block copolymer of
polypropylene oxide-polyethylene oxide. A dosage kit that includes
the injectable, nonaqueous suspension and a method of administering
the injectable, nonaqueous suspension are also disclosed.
Inventors: |
Houston; Paul R.; (Hayward,
CA) ; Chen; Guohua; (Sunnyvale, CA) ; Luk;
Andrew; (Pleasanton, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Durect Corporation |
Cupertino |
CA |
US |
|
|
Assignee: |
Durect Corporation
Cupertino
CA
|
Family ID: |
39564057 |
Appl. No.: |
14/960302 |
Filed: |
December 4, 2015 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14341713 |
Jul 25, 2014 |
|
|
|
14960302 |
|
|
|
|
13282416 |
Oct 26, 2011 |
8802095 |
|
|
14341713 |
|
|
|
|
12020372 |
Jan 25, 2008 |
|
|
|
13282416 |
|
|
|
|
60897643 |
Jan 26, 2007 |
|
|
|
Current U.S.
Class: |
424/142.1 ;
424/94.61; 514/15.2 |
Current CPC
Class: |
A61K 38/385 20130101;
A61K 9/19 20130101; C07K 2317/21 20130101; A61P 35/00 20180101;
C07K 2317/31 20130101; A61K 39/3955 20130101; C07K 16/244 20130101;
A61K 9/0019 20130101; A61K 38/47 20130101; A61K 47/26 20130101;
A61K 9/10 20130101; A61K 9/08 20130101; A61K 47/10 20130101; C12Y
302/01017 20130101; A61K 47/44 20130101; A61K 47/14 20130101; C07K
2317/94 20130101; A61K 2039/505 20130101; A61K 47/34 20130101 |
International
Class: |
A61K 47/44 20060101
A61K047/44; A61K 9/00 20060101 A61K009/00; C07K 16/24 20060101
C07K016/24; A61K 39/395 20060101 A61K039/395; A61K 38/47 20060101
A61K038/47; A61K 38/38 20060101 A61K038/38 |
Claims
1. An injectable, nonaqueous suspension comprising at least one
therapeutic agent suspended in a single component vehicle having an
amphiphilic material.
2. The injectable, nonaqueous suspension of claim 1, wherein the
single component vehicle comprises a polyethoxylated castor oil or
derivative thereof, a polyoxyethylene alkyl ether, a
polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene
stearate, a block copolymer of polyethylene oxide-polypropylene
oxide-polyethylene oxide, a block copolymer of polypropylene
oxide-polyethylene oxide-polypropylene oxide, a tetra-functional
block copolymer of polyethylene oxide-polypropylene oxide, or a
tetra-functional block copolymer of polypropylene
oxide-polyethylene oxide.
3. The injectable, nonaqueous suspension of claim 1, wherein the
single component vehicle comprises a reaction product of castor oil
with ethylene oxide in a molar ratio of 1 to 35 or a reaction
product of castor oil with ethylene oxide in a molar ratio of 1 to
45.
4. The injectable, nonaqueous suspension of claim 1, wherein the at
least one therapeutic agent comprises a small molecule, protein,
antibody, mimetibody, monoclonal antibody, antibody fragment,
peptide, nucleotide, DNA fragment, RNA fragment, plasmid fragment,
nucleotide fragment, or mixtures thereof.
5. The injectable, nonaqueous suspension of claim 1, wherein the at
least one therapeutic agent is present at a concentration that
ranges from greater than or equal to approximately 50 mg/ml to
approximately 500 mg/ml.
6. The injectable, nonaqueous suspension of claim 1, wherein the at
least one therapeutic agent comprises from approximately 5% by
weight of a total weight of the injectable, nonaqueous suspension
to approximately 50% by weight of the total weight of the
injectable, nonaqueous suspension.
7. The injectable, nonaqueous suspension of claim 1, further
comprising at least one antioxidant.
8. The injectable, nonaqueous suspension of claim 1, wherein the
suspension has an injection force that is less than or equal to
about 50 lbf.
9. The injectable, nonaqueous suspension of claim 1, wherein the
single component vehicle comprises a polyethoxylated castor oil or
derivative thereof and the at least one therapeutic agent comprises
a monoclonal antibody.
10. A dosage kit comprising a syringe and an injectable, nonaqueous
suspension, the injectable, nonaqueous suspension comprising at
least one therapeutic agent suspended in a single component vehicle
having an amphiphilic material.
11. The dosage kit of claim 10, wherein the single component
vehicle comprises a polyethoxylated castor oil or derivative
thereof, a polyoxyethylene alkyl ether, a polyoxyethylene sorbitan
fatty acid ester, a polyoxyethylene stearate, a block copolymer of
polyethylene oxide-polypropylene oxide-polyethylene oxide, a block
copolymer of polypropylene oxide-polyethylene oxide-polypropylene
oxide, a tetra-functional block copolymer of polyethylene
oxide-polypropylene oxide, or a tetra-functional block copolymer of
polypropylene oxide-polyethylene oxide.
12. The dosage kit of claim 10, wherein the at least one
therapeutic agent comprises a small molecule, protein, antibody,
mimetibody, monoclonal antibody, antibody fragment, peptide,
nucleotide, DNA fragment, RNA fragment, plasmid fragment,
nucleotide fragment, or mixtures thereof.
13. A method of administering a therapeutic agent, comprising:
suspending at least one therapeutic agent in a single component
amphiphilic vehicle to form an injectable, nonaqueous suspension;
and injecting the injectable, nonaqueous suspension into a patient
in need thereof.
14. The method of claim 13, wherein suspending at least one
therapeutic agent in a single component vehicle comprises
suspending the at least one therapeutic agent in a single component
vehicle selected from the group consisting of a polyethoxylated
castor oil or derivative thereof, a polyoxyethylene alkyl ether, a
polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene
stearate, a block copolymer of polyethylene oxide-polypropylene
oxide-polyethylene oxide, a block copolymer of polypropylene
oxide-polyethylene oxide-polypropylene oxide, a tetra-functional
block copolymer of polyethylene oxide-polypropylene oxide, and a
tetra-functional block copolymer of polypropylene
oxide-polyethylene oxide.
15. The method of claim 13, wherein suspending at least one
therapeutic agent in a single component vehicle comprises
suspending the at least one therapeutic agent in a reaction product
of castor oil with ethylene oxide in a molar ratio of 1 to 35 or in
a reaction product of castor oil with ethylene oxide in a molar
ratio of 1 to 45.
16. The method of claim 13, wherein suspending at least one
therapeutic agent in a single component vehicle comprises
suspending a small molecule, protein, antibody, mimetibody,
monoclonal antibody, antibody fragment, peptide, nucleotide, DNA
fragment, RNA fragment, plasmid fragment, nucleotide fragment, or
mixtures thereof in the single component vehicle.
17. The method of claim 13, wherein the at least one therapeutic
agent is present at a concentration that ranges from greater than
or equal to approximately 50 mg/ml to approximately 500 mg/ml.
18. The method of claim 13, wherein the at least one therapeutic
agent comprises from approximately 5% by weight of a total weight
of the injectable, nonaqueous suspension to approximately 50% by
weight of the total weight of the injectable, nonaqueous
suspension.
19. The method of claim 13, further comprising adding at least one
antioxidant to the injectable, nonaqueous suspension.
20. The method of claim 13, wherein the single component
amphiphilic vehicle comprises a polyethoxylated castor oil or
derivative thereof and the at least one therapeutic agent comprises
a monoclonal antibody.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a utility conversion and claims the
benefit under 35 U.S.C. .sctn.119(e) of U.S. Provisional Patent
Application No. 60/897,643 filed Jan. 26, 2007, entitled
"INJECTABLE, NONAQUEOUS SUSPENSION WITH HIGH CONCENTRATION OF
THERAPEUTIC AGENT."
TECHNICAL FIELD
[0002] The present invention relates to an injectable suspension
that includes a therapeutic agent. More specifically, the present
invention relates to an injectable, nonaqueous suspension that
includes the therapeutic agent suspended in a single component
vehicle.
BACKGROUND
[0003] Proteins and peptides have become powerful therapeutic
agents in the treatment of various diseases, such as cancer,
inflammatory, cardiovascular, respiratory, and infectious diseases.
However, formulation and delivery of these molecules are
challenging due to solubility and viscosity limitations. Except for
highly potent molecules, formulations of these molecules need to
contain relatively high concentrations of the protein to enable
efficacious dose levels by subcutaneous ("SC") or intramuscular
("IM") routes of administration.
[0004] Commercialization strategies often involve lyophilized
formulations that require reconstitution of the protein prior to
being delivered by injection, which can add costs and time to the
manufacturing process. Ready-to-use solution formulations of
proteins and peptides, when feasible, can minimize this
inconvenience. However, the requirement for a high concentration of
the protein adds complexity to formulation design and promotes
instability.
[0005] It has been estimated that greater than 20% of all
biopharmaceuticals currently being evaluated in clinical trials are
monoclonal antibodies ("mAbs"). In general, mAb therapies require
the delivery of between approximately 100 mg and approximately 1 g
of protein per dose. Because the high end of formulation
concentrations for mAbs is typically in the range of 50 mg/ml, such
treatments commonly require the administration of 2 to 20 ml.
Typically, such volumes are administered only through intravenous
("IV") infusion performed in a clinical or hospital setting, which
leads to poor patient compliance.
[0006] To achieve a high protein concentration, nonaqueous
suspensions of proteins have been formulated. In these
formulations, the protein is suspended in a vehicle that includes
at least two of the following: a polymer, a surfactant, and a
solvent. The formulation has a protein concentration of up to 500
mg/ml.
[0007] To expand therapeutic opportunities and increase patient
compliance, a method of achieving a high concentration of mAbs is
needed so that large protein doses are deliverable in a small
volume appropriate for SC or IM injection. One possible approach is
to prepare extremely high concentration preparations of soluble
mAbs, on the order of 150 to 250 mg/ml. However, achieving such
highly concentrated mAb solutions is problematic due to solubility
limitations and/or relatively high viscosities, which often results
in protein aggregation and poor overall stability.
[0008] Polyethoxylated castor oil (also known as polyoxyl castor
oil, polyoxyl 35 castor oil, polyoxyethylated castor oil,
macogolglycerol ricinoleate, or macrogolglyceroli ricinoleas) has
been used as a solvent for pharmaceutical compositions that include
a hydrophobic drug, such as miconazole, echinomycin, teniposide,
diazepam, althesin, or paclitaxel. The hydrophobic drug and the
polyethoxylated castor oil form a solution. To further solubilize
the hydrophobic drug, many of these pharmaceutical compositions
also include an alcohol.
[0009] There remains a need to develop highly concentrated protein
formulations to enable delivery of a variety of therapeutic
proteins in a convenient way with a small volume.
SUMMARY OF THE INVENTION
[0010] The present invention relates to an injectable, nonaqueous
suspension that includes at least one therapeutic agent suspended
in a single component vehicle.
[0011] The present invention also relates to a dosage kit that
includes a syringe and the injectable, nonaqueous suspension.
[0012] The present invention also relates to a method of
administering a therapeutic agent that includes suspending the at
least one therapeutic agent in the single component vehicle and
injecting the injectable, nonaqueous suspension into a patient in
need thereof.
BRIEF DESCRIPTION OF DRAWINGS
[0013] While the specification concludes with claims particularly
pointing out and distinctly claiming that which is regarded as the
present invention, the advantages of this invention may be more
readily ascertained from the following description of the invention
when read in conjunction with the accompanying drawings in
which:
[0014] FIG. 1 is a graph showing in vitro release data for a bovine
serum albumin ("BSA")/Cremophor.RTM. ELP formulation;
[0015] FIG. 2 is a graph showing injection force data for a
BSA/Cremophor.RTM. ELP formulation;
[0016] FIG. 3 is a graph showing injection force data for a
BSA/Cremophor.RTM. RH 40 formulation;
[0017] FIG. 4 is a graph showing stability data for a monoclonal
antibody ("mAb") CNTO 1275/Cremophor.RTM. ELP formulation; and
[0018] FIG. 5 is a graph showing biocompatibility data for
Cremophor.RTM. ELP.
DETAILED DESCRIPTION OF THE INVENTION
[0019] An injectable, nonaqueous suspension having at least one
therapeutic agent and a single component vehicle is disclosed. The
therapeutic agent is suspended in the single component vehicle. The
injectable, nonaqueous suspension may be formulated to administer a
high dose of the therapeutic agent in a small dose volume. For
instance, the dose volume may be less than or equal to
approximately 2 ml/injection. The injectable, nonaqueous suspension
may provide immediate delivery of a low potency, therapeutic
agent.
[0020] As used herein, the term "therapeutic agent" refers to a
compound that provides a desired biological or pharmacological
effect when administered to a human or animal. The therapeutic
agent may be present as a solid in a dosage form of the injectable,
nonaqueous suspension. The therapeutic agent may be minimally
soluble or swellable in the single component vehicle, maintaining
the therapeutic agent in a substantially solid form in the
injectable, nonaqueous suspension. The solubility of the
therapeutic agent in the injectable, nonaqueous suspension may be
less than approximately 1% by weight ("wt %"), such as less than
approximately 0.5 wt % or less than approximately 0.1 wt %. The
therapeutic agent remains suspended in the injectable, nonaqueous
suspension independent of the therapeutic agent's molecular
structure or molecular weight. For the sake of example only, the
therapeutic agent may be a small molecule, protein, antibody,
mimetibody, mAb, antibody fragment (including a diabody, triabody,
or tetrabody), peptide, enzyme, nucleotide, DNA fragment, RNA
fragment, plasmid fragment, nucleotide fragment, or mixtures
thereof. In one embodiment, the therapeutic agent is a mAb, such as
CNTO 1275 or CNTO 148. CNTO 1275 is a human mAb to
anti-IL-12/23p40, and is described in U.S. Pat. No. 6,902,734, the
contents of which are hereby incorporated herein by this reference.
CNTO 148 is an antibody against human TNF-a, and is described in
U.S. patent application Ser. No. 09/920,137, filed Aug. 1, 2001,
entitled "Anti-TNF Antibodies, Compositions, Methods and Uses," the
contents of which are hereby incorporated herein by this reference.
In another embodiment, the therapeutic agent is a protein or
enzyme, such as BSA or lysozyme.
[0021] Alternatively, the therapeutic agent may be selected from
the group consisting of baclofen, glial-cell line-derived
neurotrophic factor, a neurotrophic factor, conatonkin G,
Ziconotide, clonidine, axokine, an antisense oligonucleotide,
adrenocorticotropic hormone, angiotensin I, angiotensin II, atrial
natriuretic peptide, B-natriuretic peptide, bombesin, bradykinin,
calcitonin, cerebellin, dynorphin N, alpha endorphin, beta
endorphin, endothelin, enkephalin, epidermal growth factor,
fertirelin, follicular gonadotropin releasing peptide, galanin,
glucagon, glucagon-like peptido-1, gonadorelin, gonadotropin,
goserelin, growth hormone releasing peptide, histrelin, human
growth hormone, insulin, an alpha-, beta-, or omega-interferon,
Nesiritide, leuprolide, luteinizing hormone-releasing hormone,
motilin, nafarelin, neurotensin, oxytocin, relaxin, somatostatin,
substance P, tumor necrosis factor, triptorelin, vasopressin,
growth hormone, nerve growth factor, a blood clotting factor, and a
ribozyme. In one embodiment, the at least one solvent is benzyl
benzoate, the at least one polymer is polyvinylpyrrolidone, and the
active agent is omega-interferon (omega-INF). The active agent may
also be selected from small molecules such as, for example,
ocaperidone, risperidone, and paliperidone.
[0022] The therapeutic agent may be formulated into particles
having a particle size that ranges from approximately 0.1 .mu.m to
approximately 250 .mu.m. The particles of the therapeutic agent may
be produced by conventional processes including, but not limited
to, mechanical milling and sieving or spray drying. To provide
additional stability to the therapeutic agent, a stabilizer may,
optionally, be present in the injectable, nonaqueous suspension.
The stabilizer of the therapeutic agent may be a sugar, such as
sucrose, trehalose, sorbitol, mannitol, a monosaccharide alcohol,
or mixtures thereof. If the therapeutic agent is a protein, the
therapeutic agent and, optionally, the stabilizer may be dissolved
into a solution, which is lyophilized to produce particles of the
therapeutic agent. These particles are ground and sieved to the
desired particle size. Alternatively, the solution may be
spray-dried or spray-freeze-dried to produce particles of the
desired size. In addition to the stabilizer, the formulation of the
therapeutic agent may, optionally, include at least one pH
modifier.
[0023] The single component vehicle may be a single amphiphilic
material having a liquid to semi-solid form. The amphiphilic
material may be a solvent, surfactant, or excipient. As used
herein, the term "single component vehicle" refers to a
one-component vehicle. As such, the single component vehicle does
not include additional solvents, surfactants, or excipients, which
simplifies formulation of the injectable, nonaqueous suspension. As
used herein, the term "amphiphilic" refers to a compound having a
polar, water-soluble group attached to a nonpolar, water-insoluble
group or chain. The term "liquid to semi-solid" refers to a
material having intermediate properties, such as viscosity, between
those of a solid and a liquid. The viscosity of the single
component vehicle may be selected to provide the injectable,
nonaqueous suspension with a low injection force when administered
to a human or animal. The single component vehicle may have a
melting point or a pour point of approximately room temperature
(approximately 25.degree. C.), so that the single component vehicle
is a liquid or semi-solid at body temperature.
[0024] Examples of amphiphilic materials that may be used as the
single component vehicle include, but are not limited to, a
polyethoxylated castor oil or derivative thereof (collectively
referred to herein as a "polyethoxylated castor oil"), a
polyoxyethylene alkyl ether, a polyoxyethylene sorbitan fatty acid
ester, a polyoxyethylene stearate, a block copolymer of
polyethylene oxide ("PEO")-polypropylene oxide ("PPO")-PEO, a block
copolymer of PPO-PEO-PPO, a tetra-functional block copolymer of
PEO-PPO, such as (PEO-PPO).sub.2-(PPO-PEO).sub.2, or a
tetra-functional block copolymer of PPO-PEO, such as
(PPO-PEO).sub.2-(PEO-PPO).sub.2. In one embodiment, the single
component vehicle is a polyethoxylated castor oil.
[0025] One example of a polyethoxylated castor oil is sold under
the tradename Cremophor.RTM. and is commercially available from
BASF Corp. (Mount Olive, N.J.). Cremophor.RTM. products of various
purities and viscosities are produced by BASF Corp. and may be used
in the present invention, such as Cremophor.RTM. A 25,
Cremophor.RTM. A 6, Cremophor.RTM. EL, Cremophor.RTM. RH 40,
Cremophor.RTM. ELP, or mixtures thereof. Cremophor.RTM. ELP and
Cremophor.RTM. EL are nonionic solubilizers and emulsifiers
produced by reacting castor oil with ethylene oxide in a molar
ratio of 1 to 35. Cremophor.RTM. RH 40 is a nonionic solubilizer
and emulsifier produced by reacting castor oil with ethylene oxide
in a molar ratio of 1 to 45. While the composition of
Cremophor.RTM. products is proprietary, it is believed that the
reaction product of castor oil and ethylene oxide includes a
complex mixture of unmodified castor oil and a variety of
polyethylene glycols, polyethoxylated glycerol, polyethoxylated
fatty acids, and mono-, di- and triesters of glycerol that are
polyethoxylated to differing degrees. In one embodiment, the single
component vehicle is Cremophor.RTM. ELP, which has a viscosity of
between approximately 600 mPasec and approximately 750 mPasec at
25.degree. C. In another embodiment, the single component vehicle
is Cremophor.RTM. EL, which has a viscosity of between
approximately 700 mPasec and approximately 800 mPasec at 25.degree.
C. In another embodiment, the single component vehicle is
Cremophor.RTM. RH 40. A 30% a aqueous solution of Cremophor.RTM. RH
40 has a Hoeppler viscosity at 25.degree. C. of between
approximately 20 mPasec and approximately 40 mPasec.
[0026] Examples of polyoxyethylene alkyl ethers that may be used as
the single component vehicle include, but are not limited to,
Brij.RTM. 35, Brij.RTM. 52, Brij.RTM. 56, Brij.RTM. 93, Brij.RTM.
97, Brij.RTM. 99, Ethylan.RTM. 256, Ethylan.RTM. 257, Ethylan.RTM.
2512, Renex.RTM. 30, Renex.RTM. 31, Texofor AP, Texofor A6, Texofor
A10, or mixtures thereof. Examples of polyoxyethylene sorbitan
fatty acid esters include, but are not limited to, polysorbate 61,
polysorbate 65, polysorbate 80, or mixtures thereof. Examples of
polyoxyethylene stearates include, but are not limited to, polyoxyl
6 stearate, polyoxyl 8 stearate, polyoxyl 12 stearate, polyoxyl 20
stearate, polyoxyl 40 stearate, polyoxyl 12 distearate, or mixtures
thereof. Examples of PEO-PPO-PEO include, but are not limited to,
Pluronic.RTM. L44, Pluronic.RTM. L64, Pluronic.RTM. L122,
Pluronic.RTM. P65, Pluronic.RTM. P75, Pluronic.RTM. P84,
Pluronic.RTM. P85, Pluronic.RTM. P103, Pluronic.RTM. P104,
Pluronic.RTM. P105, Pluronic.RTM. P123, or mixtures thereof.
Examples of PPO-PEO-PPO include, but are not limited to,
Pluronic.RTM. R 10R5, Pluronic.RTM. 17R4, Pluronic.RTM. 22R4,
Pluronic.RTM. 25R4, Pluronic.RTM. 25R5, Pluronic.RTM. 31R4, or
mixtures thereof. Examples of (PEO-PPO)-(PPO-PEO).sub.z include,
but are not limited to, Tetronic.RTM. 704, Tetronic.RTM.904,
Tetronic.RTM. 1104, or mixtures thereof. Examples of
(PPO-PEO).sub.2-(PEO-PPO).sub.2 include, but are not limited to,
Tetronic.RTM. R 50R8, Tetronic.RTM. 90R4, Tetronic.RTM. 150R4, or
mixtures thereof.
[0027] A high concentration of the therapeutic agent may be
suspended in the single component vehicle, enabling delivery of the
therapeutic agent in a relatively small volume. For instance, the
therapeutic agent may be present in the injectable, nonaqueous
suspension at a concentration of up to approximately 500 mg/ml. For
instance, the therapeutic agent may be present in the injectable,
nonaqueous suspension at a concentration that ranges from greater
than or equal to approximately 50 mg/ml to approximately 500 mg/ml.
Such high concentrations of therapeutic agent would not be
achievable in an aqueous formulation. Since the therapeutic agent
is present at such a high concentration, the injectable, nonaqueous
suspension may be used to deliver a therapeutic agent that has a
low potency.
[0028] In a particular embodiment, the therapeutic agent may
account for from approximately 5% by weight ("wt %") of a total
weight of the injectable, nonaqueous suspension to approximately 50
wt % of the total weight of the injectable, nonaqueous suspension.
For instance, the therapeutic agent loading may range from
approximately 10 wt % of the total weight of the injectable,
nonaqueous suspension to approximately 50 wt % of the total weight
of the injectable, nonaqueous suspension.
[0029] The injectable, nonaqueous suspension may be produced by
mixing the particles of the therapeutic agent into the single
component vehicle by techniques known in the art. Since the
therapeutic agent and the single component vehicle are combined
using conventional techniques, production of the injectable,
nonaqueous suspension is not described in detail herein. The
particles of the therapeutic agent may be substantially
homogeneously dispersed in the single component vehicle, producing
a substantially homogeneous injectable, nonaqueous suspension.
[0030] The injectable, nonaqueous suspension may, optionally,
include a small amount of at least one antioxidant. The antioxidant
may be d-alpha tocopherol acetate, dl-alpha tocopherol, ascorbyl
palmitate, butylated hydroxyanidole, ascorbic acid, butylated
hydroxyanisole, butylatedhydroxyquinone, butylhydroxyanisol,
hydroxycomarin, butylated hydroxytoluene, cephalm, ethyl gallate,
propyl gallate, octyl gallate, lauryl gallate,
propylhydroxybenzoate, trihydroxybutylrophenone, dimethylphenol,
diterlbulylphenol, vitamin E, lecithin, ethanolamine, or mixtures
thereof. If an antioxidant is present in the injectable, nonaqueous
suspension, the antioxidant may be premixed with the therapeutic
agent before mixing with the single component vehicle.
Alternatively, the antioxidant may be premixed with the single
component vehicle before mixing with the therapeutic agent or may
be loaded separately into the single component vehicle.
[0031] The injectable, nonaqueous suspension may be preloaded in a
syringe and, therefore, is injection ready without mixing or
reconstitution. The injectable, nonaqueous suspension may be loaded
into the syringe by conventional techniques, which are well known
in the art and, thus, are not described in detail herein. Since the
therapeutic agent remains in a substantially solid form, the
injectable, nonaqueous suspension can have a long shelf life
stability. The injectable, nonaqueous suspension may be fluidly
injectable at 25.degree. C. The injectable, nonaqueous suspension
in the preloaded syringe may be injected by hand. Alternatively,
the preloaded syringe may be used with an autoinjector, where
injection of the injectable, nonaqueous suspension is powered by
the mechanical force of the autoinjector.
[0032] A dosage kit that includes the injectable, nonaqueous
suspension and at least one syringe is also disclosed. In one
embodiment, the syringe is an auto-injector syringe. In another
embodiment, the syringe is divided such that the therapeutic agent
and the single component vehicle remain separate until being mixed
before injection. In another embodiment, two syringes are provided
in the dosage kit. One syringe may contain the therapeutic agent
while the other syringe may contain the single component vehicle.
The contents of the first and second syringes may be combined
before injection. The injectable, nonaqueous suspension may be
administered to a patient or animal by any route, such as by SC or
IM administration. Since the single component vehicle has a low
viscosity, the injectable, nonaqueous suspension may have a low
injection force. For instance, the injection force may be less than
or equal to approximately 50 lbf; such as less than or equal to
approximately 30 lbf or less than or equal to approximately 20
lbf.
[0033] The following examples serve to explain embodiments of the
present invention in more detail. These examples are not to be
construed as being exhaustive or exclusive as to the scope of this
invention.
EXAMPLES
[0034] In vitro release experiments were conducted to test
suspension formulations to demonstrate release of the therapeutic
agent into a buffer solution. The in vitro release characteristics
are related to in vivo release characteristics. Injection force
experiments were performed to test the injectability of the
suspension formulations because injectability is an important
performance characteristic. Stability is also an important
performance characteristic for suspension formulations. Therefore,
sampling was conducted at extended time intervals to demonstrate
stability of the therapeutic agent. Biocompatibility tests were
also conducted to demonstrate tolerance to the suspension injection
in a rat model.
Example 1
Preparation of Lysozyme Particles
[0035] A lysozyme solution was prepared by dissolving lysozyme
(available from Sigma-Aldrich Corp. (St. Louis, Mo.)) in 6.5 mM
sodium phosphate buffer, pH 6.0, at a protein concentration of 65
mg/mL. Sucrose and Tween 80 (or polysorbate 80) were optionally
added to the lysozyme solution with the concentration of sucrose
and Tween 80 in the final solution of 0%-5.5% and 0%-0.0065%
weight/volume, respectively. The lysozyme solution was lyophilized
according to the conditions shown in Table 1.
TABLE-US-00001 TABLE 1 Lyophilization Conditions for the
Preparation of Lysozyme Particles. Chamber Pressure Hold Time
Process Step Shelf Temperature (.degree. C.) (mBar) (hours) Loading
+5 N/A 2 Freezing -50 (rate 0.5.degree. C.) N/A 2 Freezing -50 N/A
2.5 Vacuum on -50 120 mT 0.5 Vacuum hold -50 120 mT 0.5 1.degree.
Drying -10 (rate 1.degree. C./minute) 120 mT 0.75 1.degree. Drying
-10 120 mT 24 2.degree. Drying 0 (rate 0.1.degree. C./minute) 80 mT
1.7 2.degree. Drying 0 80 mT 2 2.degree. Drying +35 (rate
0.25.degree. C./minute) 80 mT 2.3 2.degree. Drying +35 80 mT 10
2.degree. Drying +20 (rate 1.degree. C./minute) 80 mT 0.25
2.degree. Drying +20 80 mT 2 Minimum Total time = 50.5 hours
[0036] Lysozyme particles having the desired particle size were
prepared by grinding the lyophilized lysozyme in a Waring blender
and passing the particles through a series of sieves having
determined mesh sizes. Lysozyme particles having a particle size of
less than approximately 38 .mu.m, between from approximately 38
.mu.m to approximately 63 .mu.m, less than approximately 125 .mu.m,
and less than approximately 250 .mu.m were produced by this
process. Alternatively, lysozyme particles were prepared by
diluting the lyophilized lysozyme described above to a
concentration of approximately 20 mg/ml with deionized water and
spray drying the solution, resulting in lysozyme particles having a
particle size that ranged from approximately 1 .mu.m to
approximately 10 .mu.m.
Example 2
Preparation of BSA Particles
[0037] BSA particles were produced according to the methods
described in Example 1, except hat BSA was used in place of
lysozyme.
Example 3
Preparation of CNTO 1275 Particles
[0038] Particles of a mAb were produced by dissolving CNTO 1275 in
6.5 mM sodium phosphate buffer with sucrose (concentration of 5.5%
w/v), pH 6.0, with a protein concentration of 65 mg/mL. To the
solution of CNTO 1275 was added 0.0065% w/v of Tween 80 (or
polysorbate 80). The solution was lyophilized according to the
conditions shown in Table 2.
TABLE-US-00002 TABLE 2 Lyophilization Conditions for Preparation of
CNTO 1275 Particles. Chamber Pressure Hold Time Process Step Shelf
Temperature (.degree. C.) (mBar) (hours) Loading +5 N/A 2 Freezing
-50 (rate 0.5.degree. C.) N/A 2 Freezing -50 N/A 2.5 Vacuum on -50
120 mT 0.5 Vacuum hold -50 120 mT 0.5 1.degree. Drying -10 (rate
1.degree. C./minute) 120 mT 0.75 1.degree. Drying -10 120 mT 24
2.degree. Drying 0 (rate 0.1.degree. C./minute) 80 mT 1.7 2.degree.
Drying 0 80 mT 2 2.degree. Drying +35 (rate 0.25.degree. C./minute)
80 mT 2.3 2.degree. Drying +35 80 mT 10 2.degree. Drying +20 (rate
1.degree. C./minute) 80 mT 0.25 2.degree. Drying +20 80 mT 2
Minimum Total time = 50.5 hours
[0039] CNTO 1275 particles having a particle size of less than
approximately 125 .mu.m were prepared by grinding the lyophilized
formulation in a Waring blender and sieving through a 120 mesh
sieve.
Example 4
Preparation of Nonaqueous Suspensions
[0040] Nonaqueous suspensions of lysozyme, BSA, or CNTO 1275
particles were prepared. The particles (lysozyme, BSA, or CNTO
1275), which were prepared as described in Examples 1-3, were mixed
with Cremophor.RTM. ELP or Cremophor.RTM. RH 40 using an overhead
mixer. The mixing was performed at room temperature inside a dry
box. The particles and Cremophor.RTM. ELP or Cremophor.RTM. RH 40
were weighed and transferred into a 25 cc glass syringe. The
particle loading was from approximately 20 wt % to approximately 50
wt %, resulting in a protein concentration in a final formulation
of from approximately 120 mg/ml to approximately 500 mg/mL. An
electric stirrer with a stainless steel spatula blade was used to
blend the particles into the Cremophor.RTM. ELP or Cremophor.RTM.
RH 40 at from approximately 50 rpm to approximately 300 rpm for
approximately 5 minutes. The suspensions were filled into glass
injection syringes, yielding an injection ready dosage form. The
suspensions were stored at a refrigerated temperature
(approximately 4.degree. C. to approximately 5.degree. C.) prior to
injection.
Example 5
In Vitro Release Testing of a BSA/Cremophor.RTM. ELP
Formulation
[0041] Spray-dried BSA particles were mixed with Cremophor.RTM. ELP
at a ratio of 37 wt % BSA particles and 63 wt % Cremophor.RTM. ELP.
Three 50-60 mg samples of the BSA/Cremophor.RTM. ELP suspension
were placed in vials along with PBS buffer solution. The vials were
placed on a shaker in a 37.degree. C. oven. Samples of the
supernatant were removed from the vials at various time points to
determine the BSA content, and fresh PBS solution of the same
(removed) volume was added back to the vials. The supernatant was
analyzed using UV Spectroscopy to determine the BSA content. A
graph of the cumulative protein released versus time is shown in
FIG. 1. Approximately 95% of the BSA was released from the
suspension within approximately 20 minutes of the test initiation,
indicating the protein in the suspension of Cremophor.RTM. ELP was
released into the medium instantaneously. As such, the
Cremophor.RTM. ELP does not trap the therapeutic agent to cause a
depot effect.
Example 6
Injection Force Testing of BSA/Cremophor.RTM. ELP Formulation
[0042] Injectability of a BSA/Cremophor.RTM. ELP suspension was
determined by measuring the force required to push the suspension
through a fine gauge needle. Cremophor.RTM. ELP and BSA particles
having a particle size of less than or equal to approximately 125
.mu.m were blended in a ratio of 60:40 by weight, respectively. The
suspension was loaded into three Hamilton 500 .mu.l Gastight.RTM.
syringes. The syringes were filled with approximately 0.4 cc of the
suspension and aluminum hub hypodermic needles (21-gauge, 1 inch
(2.54 cm) in size) were placed on each syringe. The syringes were
packaged, three syringes to each polyethane bag, and stored in the
refrigerator at approximately 5.degree. C. At 1-, 5-, 28-, and
36-week time periods, samples were removed from the refrigerator
for injection force testing. The syringes were equilibrated to room
temperature (approximately 25.degree. C.) for at least two hours
before testing. The injection rate was set at approximately 1
ml/minute, which is equivalent to a crosshead speed of 4.7 inch
(11.938 cm)/minute. The injection testing was conducted at room
temperature and the peak (maximum) force value was recorded.
Injection force testing was carried out on a Mini-55 Instron
tensile testing instrument.
[0043] The injection force at room temperature versus storage time
at 5.degree. C. for the BSA/Cremophor.RTM. ELP suspension is shown
in FIG. 2. No increase in the force required to dispense the
BSA/Cremophor.RTM. ELP suspension was observed as a function of
storage time, which demonstrates that the BSA/Cremophor.RTM. ELP
suspension is physically stable in the described time frames. No
settling of the BSA particles in the Cremophor.RTM. ELP was
observed.
Example 7
Injection Force Testing of BSA/Cremophor.RTM. RH 40 Suspension
[0044] Injectability of a BSA/Cremophor.RTM. RH 40 suspension was
determined by measuring the force required to push the suspension
through a fine gauge needle. Cremophor.RTM. RH 40 and BSA particles
having a particle size of less than or equal to approximately 125
.mu.m were blended in a ratio of 60:40 by weight, respectively. The
suspension was loaded into three Hamilton 500 .mu.l Gastight.RTM.
syringes. The syringes were filled with approximately 0.4 cc of the
suspension and aluminum hub hypodermic needles (21-gauge, 1 inch
(2.54 cm) in size) were placed on each syringe. The syringes were
packaged, three syringes to each polyethane bag, and stored in the
refrigerator at approximately 5.degree. C. Samples were removed
from the refrigerator at 5 days and at 180 days for the injection
force testing. The syringes were equilibrated to room temperature
for at least two hours before the testing. The injection rate was
set at approximately 1 ml/minute, which is equivalent to a
crosshead speed of 4.7 inch (11.938 cm)/minute. The injection
testing was conducted at room temperature and the peak (maximum)
force value was recorded. Injection force testing was carried out
on a Mini-55 Instron tensile testing instrument.
[0045] The injection force at room temperature versus storage time
at 5.degree. C. for the BSA/Cremophor.RTM. RH 40 suspension is
shown in FIG. 3. No increase in the force required to dispense the
BSA/Cremophor.RTM. RH 40 suspension was observed as a function of
storage time, which demonstrates that the BSA/Cremophor.RTM. RH 40
suspension is physically stable in these time frames. No settling
of the BSA particles in the Cremophor.RTM. RH 40 was observed.
Example 8
Stability of CNTO 1275/Cremophor.RTM. ELP Formulation
[0046] Cremophor.RTM. ELP was cleaned with aluminum oxide powder to
reduce the peroxide level and was passed through sterile, 0.2 .mu.m
PTFE filters. Two 10 mg portions of CNTO 1275 were weighed into
vials for each stability time point. Into each vial, 0.1 ml of
cleaned Cremophor.RTM. ELP was added. The CNTO 1275/Cremophor.RTM.
ELP samples were then mechanically stirred and caps were placed on
each vial. The vials were removed from the dry box and placed in a
refrigerator at 5.degree. C. CNTO 1275 particles, without
Cremophor.RTM. ELP, were stored with the suspension samples as a
control. A control formulation that included 25%
polyvinylpyrollidone ("PVP") and 75% ultrapure polyethylene glycol
400 ("PEG 400") was also stored with the suspension samples. At 0-,
1-, 4-, 8-, and 12-week intervals, samples were removed from the
refrigerator and tested for monomer content by size exclusion
chromatograph ("SEC.")
[0047] A graph of monomer content versus storage time at 5.degree.
C. is shown in FIG. 4. The results show that CNTO 1275 in
Cremophor.RTM. ELP (labeled "Cremophor.RTM. ELP" in FIG. 4) had the
same monomer content as CNTO 1275 particles without Cremophor.RTM.
ELP (labeled "CNTO 1275 Particles" in FIG. 4) at each time point,
which demonstrates that the Cremophor.RTM. ELP vehicle did not
degrade the CNTO 1275 monoclonal antibody within 12 weeks of
storage time at 5.degree. C. In comparison, significant protein
aggregation was observed with the formulation that included the
CNTO 1275 particles, 25% PVP, and 75% PEG 400, which is shown by
the reduced monomer content.
Example 9
Biocompatibility of Cremophor.RTM. ELP
[0048] Cremophor.RTM. ELP was cleaned with aluminum oxide powder to
reduce the peroxide level and was passed through sterile, 0.2 .mu.m
PTFE filters. The cleaned Cremophor.RTM. ELP was transferred into
0.25 ml autoclaved glass syringes. Each syringe was filled with
between 0.155 ml and 0.160 ml of Cremophor.RTM. ELP. The syringes
were fitted with 23 gauge, 1-inch (2.54 cm) aluminum hub hypodermic
needles to deliver a 0.100 ml subcutaneous injection into rats. The
Cremophor.RTM. ELP was administered at six injection sites. The
injection sites were qualitatively assessed for swelling and
irritation each day for two weeks. Injection sites were scored as
"0" for no swelling and irritation, "1" for minimal swelling and
irritation, "2" for mild swelling and irritation, "3" for moderate
swelling and irritation, and "4" for severe swelling and
irritation. Suspension vehicles of PVP/benzyl benzoate ("BB")
(30%/70%) and lauryl alcohol ("LA") were used as controls. A graph
of the average severity score versus study day is shown in FIG. 5.
The Cremophor.RTM. ELP injections showed no swelling at the rat
injection sites. The Cremophor.RTM. ELP received the best test
score of "0" each of the 14 days that the injection sites were
observed. In comparison, minimal to moderate swelling at the
injection sites were observed with the PVP/BB and LA controls.
[0049] While the invention may be susceptible to various
modifications and alternative forms, specific embodiments have been
shown by way of example in the drawings and have been described in
detail herein. However, it should be understood that the invention
is not intended to be limited to the particular forms disclosed.
Rather, the invention is to cover all modifications, equivalents,
and alternatives falling within the spirit and scope of the
invention as defined by the following appended claims.
* * * * *