CN111035758A

CN111035758A - Pharmaceutical composition, application thereof, sterile container and kit

Info

Publication number: CN111035758A
Application number: CN201811183097.9A
Authority: CN
Inventors: 肖伟; 王永华; 郑春丽; 刘宝石; 张璐璐; 王振中
Original assignee: Jiangsu Kanion Pharmaceutical Co Ltd
Current assignee: Jiangsu Kanion Pharmaceutical Co Ltd
Priority date: 2018-10-11
Filing date: 2018-10-11
Publication date: 2020-04-21

Abstract

The invention relates to a pharmaceutical composition, application thereof, a sterile container and a kit. The pharmaceutical composition comprises a therapeutically effective amount of sophora flavescens or an effective component of sophora flavescens and a therapeutically effective amount of at least one antibody of an immune checkpoint. The pharmaceutical composition provides opportunities for additive or synergistic effects in the treatment of cancer and reduces side effects.

Description

Pharmaceutical composition, application thereof, sterile container and kit

Technical Field

The invention relates to the field of medicines, in particular to a pharmaceutical composition, application thereof, a sterile container and a kit.

Background

Cancer refers to a malignant tumor that originates in epithelial tissues and is the disease with the highest mortality worldwide. The current cancer treatments mainly include the following six.

1. Surgical treatment, i.e. by surgical resection of tumor tissue. However, many cancers have lost their timing to resection at the time of discovery, and thus surgical treatment has had a low range of application.

2. Chemotherapy, i.e., the treatment of cancer with drugs that kill cancer cells. Most chemotherapy drugs have no specificity, so that normal tissue cells undergoing cell division can be killed at the same time, and the side effect is high.

3. Radiotherapy, also known as radiotherapy or radiotherapy, uses radiation to kill cancer cells and shrink tumors. The radiation therapy may be via external radiation therapy or internal access radiation therapy. Since cancer cells grow and divide faster than normal cells, the radiation destroys the genetic material of the cells, which prevents the growth or division of the cells and controls the growth of the cancer cells. However, the range of radiation therapy is narrow and the effect is limited to the area to be irradiated.

4. Targeted therapy, which has gained significant efficacy in the treatment of certain types of cancer since the late 90 s, is the treatment with small molecules that have abnormal or deregulated proteins specific for anticancer cells. The targeted therapy has obvious curative effect, but the appearance of the drug resistance gene is a main obstacle which prevents the drug resistance gene from further improving the curative effect at present.

5. Immunotherapy. The immunotherapy utilizes the immune mechanism in human body to resist tumor cell, and is characterized by that it utilizes immunological principle and method to raise the immunogenicity of tumor cell and sensitivity for killing effector cell, and can excite and enhance the anti-tumor immune response of body, and utilizes the immune cell and effector molecule to infuse into host body, and can cooperate with immune system of body to kill tumor and inhibit tumor growth. . A variety of immunotherapies against cancer are currently being investigated. Recent advances have been in cancer vaccine therapy and monoclonal antibody therapy, and immune cell therapy is the most recently developed therapeutic technology in recent years.

6. Traditional Chinese medicine treatment.

Among the above six methods, immunotherapy combined with chinese traditional medicine therapy has recently attracted much attention and is the focus of the field of tumor treatment.

Radix Sophorae Flavescentis, also called root of Maackia amurensis, dried ginseng, Maackia amurensis, Haohanshi branch, bitter bone, Maackia amurensis seed, etc., enters heart, liver, stomach and large intestine channels, and has the effects of clearing away heat and toxic materials, eliminating dampness, dispelling pathogenic wind and killing parasites. Originally, it was recorded in Shen nong Ben Cao Jing, which is a Chinese-style product.

In modern pharmacological applications, sophora flavescens is also a common anti-tumor Chinese herbal medicine. First, kuh-seng has a very significant anti-tumor cell effect, which is mainly attributed to matrine, oxymatrine, sophocarpine, and the like, which are specifically contained in kuh-seng. Pharmacological experiments prove that the matrine has strong anticancer activity and can inhibit the growth and the reproduction of tumor cells; oxymatrine has inhibitory effect on tumor strains of certain tumor cells; sophocarpine also has anticancer effect. The three substances are mixed according to a certain proportion to play a better anti-tumor effect and have a relatively obvious inhibiting effect on solid tumors of various cancer types. Besides, kuh-seng also has the functions of antibiosis, antiphlogosis and antianaphylaxis. Experiments prove that the sophora flavescens decoction can have obvious antibacterial and anti-inflammatory effects on various bacteria such as staphylococcus aureus, candida, vaginal mold and the like. In addition, experiments prove that the high-concentration active ingredient of the lightyellow sophora root can reduce the release of an allergic medium, can be used as an immunosuppressant and has an antiallergic effect. For some tumor patients with allergic constitution, the medicament containing the sophora flavescens can be used as a first choice medicament. The low-concentration sophora flavescens solution has a good immune activation effect and can activate the autoimmunity of an organism, so that the killing effect of an immune system on tumors is enhanced. Finally, kuh-seng has good function of increasing leucocyte, so it is often used as a rehabilitation medicine for tumor patients after radiotherapy and chemotherapy. The oxymatrine can prevent leukopenia caused by chemotherapy medicine, and peripheral leukocyte count of patients can be significantly increased by intravenous injection or intramuscular injection of 30mg/kg total matrine and 100mg/kg oxymatrine. And the number, the starting time and the duration of the leucocyte are better than those of a plurality of leucocyte increasing medicines.

Disclosure of Invention

The invention aims to provide a pharmaceutical composition, which adopts the combination of sophora flavescens and antibodies of immune check points, and the anti-tumor effect is obviously improved.

The invention provides a pharmaceutical composition, which comprises effective amount of lightyellow sophora root or active ingredients of lightyellow sophora root, and effective amount of at least one kind of antibody of immune check point.

Immune checkpoints mean a series of inhibitory pathways integrated into the immune system that minimize collateral tissue damage by maintaining self-tolerance and modulating the duration and magnitude of physiological immune responses in peripheral tissues. Tumor growth is closely linked to the modulation of immune checkpoints. Tumors can utilize immune checkpoint pathways as a major mechanism of immune evasion, particularly evasion of immune responses against T cells specific for tumor antigens. Since signal transduction of many immune checkpoints is initiated by ligand-receptor interactions, it can be easily blocked or modulated by antibodies or ligand/receptor recombinant forms.

As discussed in detail below, a number of immune checkpoints have been identified. Examples include, but are not limited to, PD-1 (apoptosis protein 1; also known as CD 279); PD-L1(PD-1 ligand; also known as B7-H1); BTLA (B and T lymphocyte attenuating factor; also known as CD 272); CDLA4 (cytotoxic T lymphocyte-associated antigen 4; also known as CD 152); TIM3 (T-cell membrane protein 3; also known as HAVCr 2); and LAG3 (lymphocyte activation gene 3; also known as CD 233). Antibodies to one or more of these immune checkpoints (e.g., anti-CTLA 4 antibodies) are contemplated for use in the combinations and methods described herein. A variety of additional immune checkpoint receptors and ligands, some of which are selectively upregulated in various types of tumor cells, are candidates for blockade and are therefore particularly suitable for combination therapy of agents such as sophora flavescens (sophora flavescens extracts and active ingredients thereof). The agent enhances the activation of the anti-tumor response.

Preferably, according to the above pharmaceutical composition, the sophora flavescens is an sophora flavescens extract, preferably an sophora flavescens extract extracted by a water decoction method, an immersion method, a percolation method, a reflux method alcohol extraction method or a solvent extraction method. The active ingredient of radix Sophorae Flavescentis is selected from one or more of oxymatrine, matrine and sophocarpine.

Wherein the water decoction method comprises: cutting or pulverizing 10-100g radix Sophorae Flavescentis into coarse powder, placing in a suitable decocting device, adding 5-50 times of water to immerse the medicinal materials, soaking for 0.5-24 h, heating to boil, maintaining slightly boiling for a certain time, separating decoction, decocting the residue for 1-4 times according to the method until the decoction is light, mixing decoctions, and concentrating to a given concentration. The impregnation method comprises the following steps: soaking solid powder or shaped solid with certain shape and size in soluble compound solution containing active component, contacting for certain time, separating residual liquid, and attaching the active component onto the solid in the form of ion or compound. The diafiltration method comprises: adding leaching solvent into the coarse powder continuously to make it permeate the medicinal powder, and making the leaching solution flow out from the lower outlet. The vehicle used includes, but is not limited to, distilled water and the like. Diafiltration methods used include, but are not limited to, mono-diafiltration, re-diafiltration, counter current diafiltration, pressure diafiltration, and the like. The alcohol extraction by the reflux method comprises the following steps: soaking radix Sophorae Flavescentis coarse powder or tablet in volatile organic solvent such as ethanol, heating the extractive solution, distilling off solvent, condensing, and flowing back into the extractor for extracting medicinal materials, and repeating the above steps until various components of radix Sophorae Flavescentis are completely extracted. The solvent extraction method comprises: according to the solubility of various components in the solvent, the solvent with high solubility to active ingredients such as oxymatrine and low solubility to components which do not need to be dissolved is selected, so that the solvent penetrates into cells from cell walls through osmosis to dissolve soluble substances, concentration difference between the inside and the outside of the cells is caused, concentrated solution in the cells continuously diffuses outwards, the solvent continuously enters the medicinal material histiocyte to and fro for multiple times, and when the concentration of the solution inside and outside the cells reaches dynamic balance, the saturated solution is filtered out, and new solvent is added, so that most of the required components can be dissolved.

The extraction method of radix Sophorae Flavescentis includes, but is not limited to, the above extraction method, and extracting effective components of radix Sophorae Flavescentis.

Preferably, the immune checkpoint is selected from one or more of CTLA4, PD-1, PD-L1, BTLA, TIM3, LAG3, A2aR and killer inhibitory receptors, according to the pharmaceutical compositions described above.

Preferably, according to the pharmaceutical composition, the administration concentration of the sophora flavescens or the active ingredients of the sophora flavescens is 20 mg/kg; the antibody administration concentration at the immune checkpoint was 200 μ g/kg.

Wherein, the sophora flavescens extract and the active sophora flavescens ingredients (including but not limited to matrine, oxymatrine and sophocarpine) can be administered by any effective route. In some embodiments, the sophora flavescens extract and the sophora flavescens active ingredient are administered by oral and parenteral injection, including gavage, intraperitoneal injection, and subcutaneous injection in certain embodiments. Antibodies to one or more immune checkpoints may also be administered by any route effective in terms of the nature of the antibody. In some embodiments, the antibodies to the immune checkpoint and sophora flavescens can be administered by the same route (e.g., intraperitoneal injection), while in other embodiments, they can be administered by different routes (e.g., sophora flavescens can be administered orally or gavage, while the antibodies to the immune checkpoint can be intraperitoneal injection).

More preferably, the pharmaceutical composition according to the above is in the form of an injection or in the form of a gastrointestinal administration.

Still more preferably, the pharmaceutical composition according to the above further comprises a pharmaceutically acceptable diluent, carrier or excipient; preferably, the excipient is an isotonic injection solution, a tablet excipient, or an oral solution excipient.

The invention also provides application of the pharmaceutical composition in preparing a medicament for treating cancer.

Preferably, the cancer is a solid tumor or a hematological disorder, preferably selected from one or more of lung cancer, melanoma, renal cancer and breast cancer, according to the use of the above.

In the treatment of cancer, particular embodiments may include administering to a subject (e.g., human, murine) a therapeutically effective amount of sophora flavescens and an immune checkpoint antibody, wherein the therapeutically effective amount of the sophora flavescens agent is sufficient to achieve a mean oxymatrine serum trough concentration of 1pg/ml to 10.0 ng/ml. In addition, administering to the subject a therapeutically effective amount of matrine, oxymatrine, and sophocarpine and an immune checkpoint antibody, wherein the therapeutically effective amount of matrine, oxymatrine, and sophocarpine is sufficient to achieve an average matrine, oxymatrine, and sophocarpine serum trough concentration of 1pg/ml to 10.0 ng/ml. In some embodiments, an average matrine, oxymatrine, and sophocarpine serum trough concentration of 1.0pg/ml to 10.0ng/ml is maintained for at least 95% of the period of time.

In some embodiments, the average matrine, oxymatrine, and sophocarpine serum trough concentration is between 1.0pg/ml to 100 pg/ml; 0.1ng/ml to 1.0 ng/ml; 1.0ng/ml to 10 ng/ml; 0.5ng/ml to 5.0 ng/ml; 0.75ng/ml to 1.25ng/ml or 0.9ng/ml to 1.1 ng/ml.

In particular embodiments, the average matrine, oxymatrine, and sophocarpine serum trough concentration is at least 1.25ng/ml, at least 1.5ng/ml, at least 1.6ng/ml, at least 1.7ng/ml, at least 1.8ng/ml, at least 1.85ng/ml, at least 1.9ng/ml, at least 1.95ng/ml, at least 1.97ng/ml, and at least 1.98ng/ml, at least 1.99ng/ml, at least 2.0ng/ml, or greater than 2 ng/ml.

In further embodiments, the aforementioned period of time is at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 6 weeks, at least 2 months, at least 3 months, at least 6 months, at least 9 months, or greater than 12 months.

In particular embodiments, the average matrine, oxymatrine, and sophocarpine serum trough concentrations are maintained for a period of at least 85%, at least 90%, at least 96%, at least 98%, at least 99%, or 100%.

It is contemplated that a dosing regimen sufficient to maintain a desired steady-state serum trough concentration may result in an initial serum trough concentration that is higher than the desired steady-state serum trough concentration. Due to the pharmacodynamic and pharmacokinetic characteristics of sophora flavescens in mammalian subjects, the initial trough concentration gradually but continuously decreases over a period of time, even if the dosing parameters (amount and frequency) remain constant. After the period of time, the gradual but sustained decline ends and the steady state serum trough concentration is maintained.

Certain embodiments relate to dosing parameters, regimens, etc., of immune checkpoint antibodies when they are administered in combination with sophora flavescens. In general, the dosing parameters and treatment regimens associated with immune checkpoint antibody monotherapy are also applicable when such agents are used in combination with sophora flavescens or an sophora flavescens active ingredient as described herein.

Certain embodiments encompass the administration of a sophora flavescens extract and a sophora flavescens active ingredient in combination with one immune checkpoint antibody, other embodiments encompass the administration of a sophora flavescens extract and a sophora flavescens active ingredient in combination with two immune checkpoint antibodies, and still further embodiments encompass the administration of a sophora flavescens extract and a sophora flavescens active ingredient in combination with three or more immune checkpoint antibodies. Such combinations may be advantageous in that the sophora flavescens extract as well as the sophora flavescens active ingredient and the immune checkpoint antibody have different mechanisms of action, which provide an opportunity to attack the underlying disease, disorder or condition from a number of different therapeutic perspectives.

The invention also provides a sterile container comprising the pharmaceutical composition; preferably, the sophora flavescens and the antibody of the immune checkpoint are separately placed or mixed placed in a sterile container; more preferably, the sterile container is a syringe or an infusion bag; the infusion bag is selected from a double-chamber bag or a single-chamber bag, the antibodies of the radix sophorae flavescentis and the immune check point are respectively placed in the first chamber and the second chamber in the double-chamber bag, and the antibodies of the radix sophorae flavescentis and the immune check point are placed in the single-chamber bag in a mixed mode.

The invention also provides a kit comprising the sterile container. Preferably, the kit further comprises a second sterile container comprising at least one additional prophylactic or therapeutic agent. More preferably, the prophylactic or therapeutic agent is a chemotherapeutic agent.

The pharmaceutical compositions of the invention provide an opportunity for additive or synergistic effects in the treatment and/or prevention of the diseases, disorders, and conditions described herein. In addition, administration of the pharmaceutical composition often allows to reduce the amount and/or frequency of administration of the sophora flavescens and other agents of the sophora flavescens active principle and combinations thereof, which may minimize or eliminate any side effects.

Drawings

FIG. 1 is the body weight change of the mice of example 1;

FIG. 2 shows the change in tumor size of the mice of example 1;

FIG. 3 is a survival statistics of mice of example 1;

fig. 4 shows the interferon expression in the model group and combination administration group of example 1, wherein: p <0.001, x: p < 0.01.

Detailed Description

The following detailed description of the present invention, taken in conjunction with the accompanying drawings and examples, is provided to enable the invention and its various aspects and advantages to be better understood. However, the specific embodiments and examples described below are for illustrative purposes only and are not limiting of the invention.

As used herein, the term "treatment" refers to any indicator of success in treating or ameliorating an injury, condition, disorder, or symptom (e.g., pain), including any objective or subjective parameter, such as elimination; improvement; reduced symptoms or making the patient more tolerant of symptoms, damage, conditions or disorders; reducing the frequency or duration of symptoms or disorders; or, in some cases, prevent the onset of symptoms or disorders. Treatment or amelioration of symptoms can be based on any objective or subjective parameter, including, for example, the results of a physical examination.

The starting materials and reagents used in the following examples are all commercially available.

Example 1

In order to prove that the medicine composition has good curative effect, animal experiments prove that the medicine composition of the lightyellow sophora root and the PD-L1 has the following improvement effect on a mouse lung cancer tumor model:

1 Material

1.1 cell culture

Lewis murine lung adenocarcinoma cells (LLC) were purchased from the cell culture center of Chinese Academy of medicine (CellCulture center Chinese academic of Medical Sciences; CAMS; the republic of China, Beijing). 90% DMEM medium (Dulbecco's modified Eagle's medium, Gibco BRL, USA), 10% FBS fetal bovine serum (total bone serum, Gibco BRL, USA), penicillin (penicilin G, 100U/mL) and streptomycin (streptomycin, 100mg/mL) were added in a medium containing 5% CO₂、95％O₂The culture is carried out in a constant temperature and humidity incubator at 37 ℃. And digesting and passaging by using 0.2% of pancreatin and 0.02% of EDTA every 3-4d when the cells grow to 70-90%.

1.2 Experimental animals

Healthy SPF-grade male C57BL/6 mice were used, and purchased from Institute of laboratory animal Science (Institute of laboratory animal Science) of CAMS, Beijing, the people's republic of China, 50 mice. The experiment was carried out with adaptive feeding for 1 week, with free intake and drinking. The temperature of the test animal room is controlled to be 22 ℃ (± 3 ℃), the relative humidity is at least kept at 30% and is not more than 70%, and the illumination for 12 hours and the darkness for 12 hours are alternately kept by adopting artificial illumination.

1.3 medicine

Oxymatrine with purity of more than 98% is purchased from Shanghai-sourced leaf Biotechnology GmbH; the name of the product is: oxymatrine; the product number B21470-20mg, 1% DMSO is used for assisting dissolution during preparation, and then dissolved in 0.9% physiological saline.

PD-L1 antibody: purchased from Bio X cells; the name, InVivo MAb anti-mouse PD-L1 (B7-H1); cargo number BE 0101; the specification is 100 mg.

IgG antibody: purchased from Bio X cells; the name InVivo MAb rat IgG2b isotype control, anti-keyhole liver hemacyanin; cargo number BE 0090.

2 method

2.1 mouse tumor model establishment

C57BL/6 mice were acclimatized for 1 week, LLC cell numberWhen enough, inoculation molding is carried out. 200. mu.l of 1X 10⁷One/ml LLC cells were injected subcutaneously into the right axilla of mice, the day of inoculation being day 0.

2.2 Experimental groups and dosing

The successfully inoculated 50C 57BL/6 mice were randomly divided into 5 groups of 10 mice each, numbered by toe clipping. After grouping, each group was fed normally every day. Experimental animals were grouped as follows:

(a) model group: no treatment is done.

(b) IgG negative control group: 20mg of IgG antibody was dissolved in 10ml buffer, i.e., 2000. mu.g/ml, and each mouse was injected intraperitoneally with 0.1ml (200. mu.g), and treated on days 1,3,6,8, and 11 with 0.1ml IgG solution.

(c) PD-L1 antibody panel: 20mg of PD-L1 antibody was dissolved in 10ml buffer, i.e., 2000. mu.g/ml, and each mouse was injected intraperitoneally with 0.1ml (200. mu.g), and on days 1,3,6,8, and 11 of treatment, intraperitoneally with 0.1ml of PD-L1 solution.

(d) Oxymatrine group: the monomer oxymatrine with purity of more than 98% is administered at a dose of 20mg/kg every time, and is administered once a day on the 1 st to 12 th days of treatment.

(4) PD-L1 antibody + oxymatrine combined administration group: the monomer oxymatrine with purity of more than 98% is administered once a day at a dose of 20mg/kg per mouse. 200ug/20g of PD-L1 antibody per mouse was injected intraperitoneally on days 1,3,6,8, and 11 of treatment.

3 Experimental indices and results statistics

Starting on the day of inoculation, mice were weighed daily and recorded until they died; tumors were measured and recorded daily using vernier caliper from the day of dosing, and tumor volume was calculated as: tumor size ═ long diameter × short diameter/2, until mice died. Tumor inhibition rate ═ model group mean volume-experimental group mean volume)/model group mean volume × 100%

The results are reported in Table 1 and FIGS. 1-2.

TABLE 1 mouse body weight (g) and tumor volume (mm)³) Average of

When the diameter of any tumor of the mouse reaches 2cm, the mouse is considered to die, and the survival period is from the beginning of tumor inoculation to the time of the death of the mouse. The results of the lifetime of each set are shown in FIG. 3.

Total RNA in mouse tumors is extracted through tissue disruption, and then the interferon expression condition in each group of tumors is determined by utilizing a QT-PCR technology. The relative expression of interferon in each group is shown in FIG. 4.

The tumor-bearing experiment of mice shows that compared with a model group, a negative control group and a single drug, the oxymatrine and the PD-L1 antibody are combined remarkably (P <0.01) to delay the tumor growth (the tumor inhibition rate of the negative control group is-8.57%, the tumor inhibition rate of the PD-L1 antibody group is 25.68%, the tumor inhibition rate of the oxymatrine group is 18.40%, and the tumor inhibition rate of the combined drug group is 41.16%) and prolong the survival period (log-rank test, P <0.05) (see figure 3). Importantly, the weight of the mice was not significantly altered by the combination, indicating that the combination did not have significant side effects of weight loss (see figure 1). And the detection of tumor tissues in the combined medicine group shows that the mRNA expression level of I-type interferon (INFA4, INFA5 and INFA16) and III-type interferon (IL28a, IL28b and IL29) is remarkably increased (see figure 4), and the combination of oxymatrine and PD-L1 antibody is helpful for improving the expression of inflammatory factors in immune microenvironment and enhancing the activity of T cells in tumor microenvironment.

Finally, it should be noted that: it should be understood that the above examples are only for clearly illustrating the present invention and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications of the invention may be made without departing from the scope of the invention.

Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of sophora flavescens or an active ingredient thereof, and a therapeutically effective amount of at least one antibody to an immune checkpoint.

2. The pharmaceutical composition of claim 1,

the radix Sophorae Flavescentis is radix Sophorae Flavescentis extract, preferably radix Sophorae Flavescentis extract extracted by water decoction, soaking, percolation, reflux alcohol extraction or solvent extraction,

the active ingredient of radix Sophorae Flavescentis is selected from one or more of oxymatrine, matrine and sophocarpine.

3. The pharmaceutical composition of claim 1, wherein the immune checkpoint is selected from one or more of CTLA4, PD-1, PD-L1, BTLA, TIM3, LAG3, A2aR, and killer inhibitory receptors.

4. The pharmaceutical composition according to claim 1, wherein the administration dose of the sophora flavescens or the active ingredient of sophora flavescens is 20 mg/kg; the antibody at the immune checkpoint is administered at a dose of 200 μ g/kg.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is in a form for injection or in a form for gastrointestinal administration.

6. The pharmaceutical composition of claim 5, further comprising a pharmaceutically acceptable diluent, carrier or excipient; preferably, the excipient is an isotonic injection solution, a tablet excipient, or an oral solution excipient.

7. Use of a pharmaceutical composition according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment of cancer.

8. Use according to claim 7, the cancer being a solid tumor or a hematological disorder, preferably selected from one or more of lung cancer, melanoma, renal cancer and breast cancer.

9. A sterile container comprising the pharmaceutical composition of any one of claims 1-6; preferably, the sophora flavescens and the antibody of the immune checkpoint are separately placed or mixed placed in a sterile container; more preferably, the sterile container is a syringe or an infusion bag.

10. A kit comprising the sterile container of claim 9; preferably, the kit further comprises a second sterile container comprising at least one additional prophylactic or therapeutic agent; more preferably, the prophylactic or therapeutic agent is a chemotherapeutic agent.