CN111184688A - Dexamethasone acetate injection and preparation method thereof - Google Patents
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Abstract
The invention relates to dexamethasone acetate injection and a preparation method thereof. Specifically, the dexamethasone acetate injection comprises active ingredients of dexamethasone acetate, sodium chloride, water for injection and the like. The invention adopts a conventional method to prepare dexamethasone acetate injection. The dexamethasone acetate injection of the invention has excellent technical effects as described in the specification.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to an injection and a preparation method thereof, and particularly relates to an injection taking dexamethasone acetate as an active component and a preparation method thereof.
Background
Dexamethasone (Dexamethasone, DXMS for short) was first synthesized in 1957, Dexamethasone sodium phosphate was produced in Merck & co in 1960, and Dexamethasone derivatives on the market so far reach more than 12, are listed in the basic drug standard list of the world health organization and are one of the essential drugs of the basic public health system.
The chemical structure of dexamethasone is that fluorine atom is introduced into the 9 α bit of the B ring of prednisolone, methyl is introduced into the 16 α bit of the D ring, 9 α fluorine and 16 α methyl both enable the anti-inflammatory activity of the dexamethasone to be obviously enhanced, and 16 α methyl remarkably reduces the water-sodium retention side effect of the dexamethasone.
Dexamethasone, like other glucocorticoids, has pharmacological actions of resisting inflammation, resisting endotoxin, suppressing immunity, resisting shock, enhancing stress reaction and the like, so that dexamethasone is widely applied to various departments for treating various diseases, such as autoimmune diseases, allergy, inflammation, asthma, dermatology and ophthalmic diseases. The dexamethasone sodium phosphate injection is an indispensable first-aid medicine for rescuing critically ill patients, and in recent ten years, clinicians use dexamethasone sodium phosphate to treat and prevent drug allergy caused by various Chinese and western medicines and treat fever caused by viral influenza and the like, so that the clinical dosage of dexamethasone is increased year by year, and China has become the largest dexamethasone market in the world.
Dexamethasone is inexpensive and typically costs less than $ 25 per month of treatment in the united states. In india, a preterm delivery requires only $ 0.5 per treatment session. Dexamethasone is readily available in most countries. Dexamethasone is an artificial corticosteroid used to treat a variety of conditions including rheumatic diseases, certain skin disorders, severe allergies, asthma, chronic obstructive pulmonary disease, laryngitis pseudomembranous, cerebral edema, and possibly in combination with antibiotics in tuberculosis patients. The product is classified as grade C during pregnancy in America, and can be administered only after the effect of the medicine is evaluated to be greater than the side effect; the classification of Australia is A, which indicates that the product is commonly used for pregnant women and there is no evidence of harm to fetus.
Dexamethasone Acetate, Dexamethasone Acetate, is a 21-bit acetic acid esterification product of Dexamethasone, and has the chemical name of 16 α -methyl-11 β,17 α, 21-trihydroxy-9 α -fluoropregna-1, 4-diene-3, 20-dione-21-Acetate, the molecular formula of which is C24H31FO6, the molecular weight of which is 434.50, and the chemical structural formula of which is:
dexamethasone acetate is white or off-white crystal or crystalline powder, and has no odor. Dexamethasone acetate is easily soluble in acetone, soluble in methanol or anhydrous ethanol, slightly soluble in ethanol or chloroform, very slightly soluble in diethyl ether, and insoluble in water.
Dexamethasone acetate injection is a preparation commonly used in clinic, and is received in various versions of Chinese pharmacopoeia. The concentration of the active drug in the injection is 5mg/ml, and three different specifications of 0.5ml, 1ml and 5ml can be clinically used. The dexamethasone acetate injection is suspension of fine particles, the fine particles sink after standing, and uniform milky suspension is formed after shaking.
Dexamethasone acetate injection is mainly used for allergic and autoimmune inflammatory diseases clinically. Such as connective tissue disease, rheumatoid arthritis, severe bronchial asthma, allergic diseases such as dermatitis, ulcerative colitis, acute leukemia, and malignant lymphoma. The usual usage amounts are, intramuscular: 1-8 mg once, 1 time a day; can also be used for intratenosynovium injection or intraarticular injection or soft tissue injury part injection, 0.8-6 mg is used once, and 1 time is carried out at two weeks intervals; local intradermal injection, 0.05-0.25 mg per spot, 2.5mg in total, 1 time a week; 0.1-0.2 mg is injected into nasal cavity, larynx, trachea, middle ear cavity and ear canal, 1-3 times per day. The storage method is to store the product in a closed and light-proof way at normal temperature, and the validity period can reach 24 months.
The raw material of dexamethasone acetate contains unesterified free dexamethasone, and dexamethasone acetate also has the possibility of hydrolysis in an aqueous medium, although free dexamethasone also has biological activity, in view of the difference between the physicochemical property of the free dexamethasone and that of the dexamethasone acetate, especially if the content of the free dexamethasone in the injection is changed, unexpected consequences can be caused on the physicochemical property of the injection. In addition, because dexamethasone acetate injection is a suspension, maintaining the stability of the particle size in the injection is also a particular concern for such injections, e.g., changes in particle size during prolonged storage are a particular concern. However, the prior art is still deficient in the art of dexamethasone acetate injection formulations, and in particular, the chemical stability and microparticle physical stability of, for example, the active ingredient in aqueous dexamethasone acetate injections, remains a desirable improvement in the art.
Disclosure of Invention
The invention aims to provide a dexamethasone acetate injection and also aims to provide a method for preparing the dexamethasone acetate injection. It has been surprisingly found that the present methods and formulations exhibit one or more of the excellent technical effects as described herein, and the present invention has been completed based on this finding.
Therefore, the invention provides dexamethasone acetate injection in a first aspect, which comprises dexamethasone acetate, sodium chloride, polysorbate 80, thimerosal, sodium carboxymethylcellulose and water for injection.
According to the dexamethasone acetate injection in the first aspect of the invention, the concentration of dexamethasone acetate is 4-6 mg/ml, such as 4.5-5.5 mg/ml, such as 5 mg/ml.
The dexamethasone acetate injection according to the first aspect of the invention, wherein the concentration of sodium chloride is 7-9 mg/ml, such as 7.5-8.5 mg/ml, such as 8 mg/ml.
The dexamethasone acetate injection solution according to the first aspect of the invention, wherein the concentration of polysorbate 80 is 1.3-1.7 mg/ml, such as 1.4-1.6 mg/ml, such as 1.5 mg/ml.
The dexamethasone acetate injection solution according to the first aspect of the invention has the concentration of thimerosal of 8-12 μ g/ml, such as 9-11 μ g/ml, such as 10 μ g/ml.
The dexamethasone acetate injection according to the first aspect of the invention, wherein the concentration of the sodium carboxymethylcellulose is 4-6 mg/ml, such as 4.5-5.5 mg/ml, such as 5 mg/ml.
The dexamethasone acetate injection according to the first aspect of the invention comprises:
4-6 mg/ml dexamethasone acetate,
7-9 mg/ml of sodium chloride,
1.3-1.7 mg/ml polysorbate 80,
8-12 mu g/ml of thimerosal,
4-6 mg/ml of sodium carboxymethylcellulose,
Water for injection is added to 1 ml.
The dexamethasone acetate injection according to the first aspect of the invention comprises:
dexamethasone acetate 4.5-5.5 mg/ml,
7.5 to 8.5mg/ml of sodium chloride,
1.4-1.6 mg/ml polysorbate 80,
9-11 mu g/ml of thimerosal,
4.5-5.5 mg/ml of sodium carboxymethylcellulose,
Water for injection was added to 1 ml.
The dexamethasone acetate injection according to the first aspect of the invention comprises:
5mg of dexamethasone acetate,
8mg of sodium chloride,
1.5mg of polysorbate 80,
10 mu g of thimerosal,
5mg of sodium carboxymethylcellulose,
Water for injection was added to 1 ml.
The dexamethasone acetate injection according to the first aspect of the invention is prepared according to a method comprising the following steps:
(1) adding sodium chloride into injection water (for example, at the temperature of 50-60 ℃) with the volume of 70-80% of the formula volume for dissolving;
(2) adding thimerosal into sodium chloride solution, stirring to dissolve, slowly adding sodium carboxymethylcellulose, stirring for dispersing, stirring to dissolve completely, filtering (for example, with 30 mesh sieve), and boiling;
(3) adding polysorbate 80 and dexamethasone acetate into the boiled solution, continuously boiling for 20-40 min to fully dissolve the liquid medicine, cooling to room temperature, and adding water for injection to 85-90% of the formula volume;
(4) shearing and circulating the liquid medicine obtained in the last step for 30-60 min by using a high-shear homogenizing emulsifying machine, then sequentially carrying out medium-pressure (500-800 bar) homogenization and high-pressure (1200-1300 bar) homogenization on the liquid medicine in a high-pressure homogenizing machine, repeatedly carrying out medium-pressure homogenization and high-pressure homogenization alternative treatment until the particle size is less than 15 mu m, adding water to full dose, and filtering (for example, using a filter element with the pore size of 75 mu m and made of polypropylene);
(5) filling the filtrate obtained in the above step into a glass bottle, sealing, and sterilizing under heat and pressure (for example, sterilizing at 115 deg.C for 30 min).
The dexamethasone acetate injection according to the first aspect of the invention further comprises glycine. In one embodiment, the concentration of glycine is 3-5 mg/ml, such as 4 mg/ml. In one embodiment, glycine is added with polysorbate 80.
The dexamethasone acetate injection according to the first aspect of the invention further comprises citric acid. In one embodiment, the concentration of citric acid is 0.5-1 mg/ml, such as 0.75 mg/ml. In one embodiment, citric acid is added with polysorbate 80. It has been found that the addition of both glycine and citric acid in the injection solution together with polysorbate 80 not only inhibits the increase in the content of free dexamethasone (dexamethasone acetate is hydrolyzed via ester bonds to form free dexamethasone), but also makes the microparticles in the injection solution more stable.
Further, the second aspect of the present invention provides a method for preparing dexamethasone acetate injection, wherein the injection comprises dexamethasone acetate, sodium chloride, polysorbate 80, thimerosal, sodium carboxymethylcellulose and water for injection, and the method comprises the following steps:
(1) adding sodium chloride into injection water (for example, at the temperature of 50-60 ℃) with the volume of 70-80% of the formula volume for dissolving;
(2) adding thimerosal into sodium chloride solution, stirring to dissolve, slowly adding sodium carboxymethylcellulose, stirring for dispersing, stirring to dissolve completely, filtering (for example, with 30 mesh sieve), and boiling;
(3) adding polysorbate 80 and dexamethasone acetate into the boiled solution, continuously boiling for 20-40 min to fully dissolve the liquid medicine, cooling to room temperature, and adding water for injection to 85-90% of the formula volume;
(4) shearing and circulating the liquid medicine obtained in the last step for 30-60 min by using a high-shear homogenizing emulsifying machine, then sequentially carrying out medium-pressure (500-800 bar) homogenization and high-pressure (1200-1300 bar) homogenization on the liquid medicine in a high-pressure homogenizing machine, repeatedly carrying out medium-pressure homogenization and high-pressure homogenization alternative treatment until the particle size is less than 15 mu m, adding water to full dose, and filtering (for example, using a filter element with the pore size of 75 mu m and made of polypropylene);
(5) filling the filtrate obtained in the above step into a glass bottle, sealing, and sterilizing under heat and pressure (for example, sterilizing at 115 deg.C for 30 min).
The method according to the second aspect of the present invention, wherein the concentration of dexamethasone acetate in the dexamethasone acetate injection is 4-6 mg/ml, such as 4.5-5.5 mg/ml, such as 5 mg/ml.
The method according to the second aspect of the present invention, wherein the concentration of sodium chloride in the dexamethasone acetate injection is 7-9 mg/ml, such as 7.5-8.5 mg/ml, such as 8 mg/ml.
The method according to the second aspect of the invention, wherein the concentration of polysorbate 80 in the dexamethasone acetate injection is 1.3-1.7 mg/ml, such as 1.4-1.6 mg/ml, such as 1.5 mg/ml.
The method according to the second aspect of the invention, wherein the concentration of thimerosal in the dexamethasone acetate injection is 8-12 μ g/ml, such as 9-11 μ g/ml, such as 10 μ g/ml.
The method according to the second aspect of the invention, wherein the concentration of the sodium carboxymethylcellulose in the dexamethasone acetate injection is 4-6 mg/ml, such as 4.5-5.5 mg/ml, such as 5 mg/ml.
The method according to the second aspect of the present invention, wherein the dexamethasone acetate injection comprises:
4-6 mg/ml dexamethasone acetate,
7-9 mg/ml of sodium chloride,
1.3-1.7 mg/ml polysorbate 80,
8-12 mu g/ml of thimerosal,
4-6 mg/ml of sodium carboxymethylcellulose,
Water for injection is added to 1 ml.
The method according to the second aspect of the present invention, wherein the dexamethasone acetate injection comprises:
dexamethasone acetate 4.5-5.5 mg/ml,
7.5 to 8.5mg/ml of sodium chloride,
1.4-1.6 mg/ml polysorbate 80,
9-11 mu g/ml of thimerosal,
4.5-5.5 mg/ml of sodium carboxymethylcellulose,
Water for injection was added to 1 ml.
The method according to the second aspect of the present invention, wherein the dexamethasone acetate injection comprises:
5mg of dexamethasone acetate,
8mg of sodium chloride,
1.5mg of polysorbate 80,
10 mu g of thimerosal,
5mg of sodium carboxymethylcellulose,
Water for injection was added to 1 ml.
The method according to the second aspect of the present invention, wherein the dexamethasone acetate injection further comprises glycine. In one embodiment, the concentration of glycine is 3-5 mg/ml, such as 4 mg/ml. In one embodiment, glycine is added with polysorbate 80.
The method according to the second aspect of the present invention, wherein the dexamethasone acetate injection further comprises citric acid. In one embodiment, the concentration of citric acid is 0.5-1 mg/ml, such as 0.75 mg/ml. In one embodiment, citric acid is added with polysorbate 80.
Any technical feature possessed by any one aspect of the invention or any embodiment of that aspect is equally applicable to any other embodiment or any embodiment of any other aspect, so long as they are not mutually inconsistent, although appropriate modifications to the respective features may be made as necessary when applicable to each other. Various aspects and features of the disclosure are described further below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
The dexamethasone acetate injection of the present invention exhibited excellent technical effects as described in the following embodiments, for example, in test example 1 and test example 2 below, a commercially available dexamethasone acetate injection (H51020723, 1ml:5mg) was measured at the same time, and as a result, the commercially available injection: no agglomeration phenomenon occurs at 0 month and 6 months, no particles with a particle size of 50 μm or more are detected at 0 month and 6 months, the proportion of large particles at 0 month is 1.8%, and the proportion of large particles at 6 months is 8.86%; the content of dexamethasone in 0 month is 0.086 percent, and the increase rate of dexamethasone in 6 months is 324.2 percent. It should be noted that, although the injection solutions obtained from the above-mentioned commercial product H51020723 and the herein examples 1 to 5 and examples 7 to 8 both meet the specification of dexamethasone acetate injection solution carried on page 1531 of chinese pharmacopoeia of 2015 edition at 0 month and 6 months, the injection solution obtained from example 6 is significantly better in terms of two parameters, namely particle size and dexamethasone content as an impurity. The 6-month test described above corresponds to an injection which has been left to stand for 24 months under the storage conditions stipulated in the pharmacopoeia, i.e. which reflects the performance of the pharmaceutical product over its entire useful life, as is well known to the person skilled in the art.
The dexamethasone acetate injection is a suspension of fine particles, the fine particles sink after standing, and the dexamethasone acetate injection is shaken to form uniform milky suspension. The traditional Chinese medicine composition is mainly used for treating allergic and autoimmune inflammatory diseases clinically. Such as connective tissue disease, rheumatoid arthritis, severe bronchial asthma, allergic diseases such as dermatitis, ulcerative colitis, acute leukemia, and malignant lymphoma. The dexamethasone acetate injection can be subpackaged into glass bottles with different volumes, such as 0.5ml, 1ml, 2ml, 5ml and other specifications per bottle. The dexamethasone acetate injection can be injected in an intramuscular mode, 1-8 mg is used once, and the injection is used 1 time a day. The dexamethasone acetate injection can also be injected into a tendon sheath or a damaged part of a joint cavity and soft tissue, wherein the dexamethasone acetate injection is 0.8-6 mg once and is 1 time at two weeks intervals. The dexamethasone acetate injection can also be injected into skin locally, each point is 0.05-0.25 mg, and the total amount is 2.5mg, and the injection is taken 1 time a week. The dexamethasone acetate injection can also be injected through nasal cavities, throats, tracheas, middle ear cavities and ear tubes: 0.1-0.2 mg, 1-3 times a day. The dexamethasone acetate injection can also be injected into the vein: generally 2-20 mg/time, 1 time per day.
The active component of the dexamethasone acetate injection is adrenocortical hormone medicine, the anti-inflammatory, anti-allergic and anti-shock effects of the dexamethasone acetate injection are more obvious than prednisone, the dexamethasone acetate injection has light effects of retaining water and sodium and promoting potassium excretion, and the dexamethasone acetate injection has strong inhibition effect on pituitary and adrenal gland. 1. Anti-inflammatory action: the product can reduce and prevent the reaction of tissues to inflammation, thereby reducing the manifestation of inflammation. Hormones inhibit the accumulation of inflammatory cells, including macrophages and leukocytes, at sites of inflammation and inhibit phagocytosis, the release of lysosomal enzymes, and the synthesis and release of chemical mediators of inflammation. Can reduce and prevent the tissue reaction to inflammation, thereby reducing the inflammation expression. 2. Immunosuppressive action: including preventing or inhibiting cell-mediated immune responses, delaying allergic responses, reducing the number of T lymphocytes, monocytes, eosinophils, reducing the binding capacity of immunoglobulins to cell surface receptors, and inhibiting the synthesis and release of interleukins, thereby reducing the conversion of T lymphocytes into lymphoblasts and reducing the spread of the primary immune response. Can reduce the passage of immune complex through the basement membrane and reduce the concentration of complement components and immunoglobulins.
Generally, peak plasma concentrations were reached 8 hours after intramuscular injection of dexamethasone acetate. The binding rate of plasma protein is lower than that of other cortical hormone drugs.
Dexamethasone can be in various forms such as proto-type medicine, dexamethasone phosphate and dexamethasone acetate, the dexamethasone phosphate can be prepared into solution type injection due to water solubility, and the dexamethasone ester can be prepared into tablet, cream and suspension type injection such as dexamethasone acetate injection described in the invention. They have some commonality in the clinic, but may differ in specific usage.
Dexamethasone, also known as fluorometholone, dexamethone, is a glucocorticoid. The derivatives of the compound have hydrocortisone, prednisone and the like, have the pharmacological actions of anti-inflammation, antitoxic, antiallergic and antirheumatic, and are widely used clinically. Is easy to be absorbed by digestive tract, the plasma T1/2 is 190 minutes, the tissue T1/2 is 3 days, and the peak values of blood concentration are reached at l hours and 8 hours respectively after dexamethasone sodium phosphate or dexamethasone acetate is injected into muscle. The product has lower plasma protein binding rate than other corticoid drugs, and the anti-inflammatory activity of 0.75mg of the product is equivalent to 5mg of prednisolone. The adrenocortical hormone medicine has stronger anti-inflammatory, antiallergic and antitoxic effects than prednisone, has light water-sodium retention and potassium discharge promoting effects, and can be injected into muscle or dripped for inhibiting pituitary-adrenal gland.
The anti-inflammatory effect and the immunosuppressive effect of dexamethasone and derivatives thereof are as detailed above, the dexamethasone oral preparation is easily absorbed by a digestive tract, the plasma T1/2 is 190 minutes, the tissue T1/2 is 3 days, blood concentration peaks are respectively reached after 1 hour and 8 hours after myo-injection of dexamethasone sodium phosphate or dexamethasone acetate, the plasma protein binding rate of the dexamethasone oral preparation is lower than that of other corticoids drugs, the anti-inflammatory activity of the dexamethasone oral preparation is equivalent to that of 5mg prednisolone, the dexamethasone oral preparation is easily absorbed by the digestive tract, the dexamethasone oral preparation can also be absorbed percutaneously, the dexamethasone sodium phosphate or dexamethasone acetate is respectively reached after 1 hour and 8 hours after intramuscular injection, the blood concentration peaks are reached, the plasma protein binding rate is lower than that of other corticoids drugs, the dexamethasone sodium phosphate or the dexamethasone acetate, the dexamethasone sodium phosphate is about 77%, the dexamethasone sodium phosphate is easy to permeate through placenta but almost not enough, the dexamethasone biological half-life is about 190 minutes, the tissue half-life is about 3 days, more than 65% of the dexamethasone is discharged from urine in 24 hours, the preparations which are mainly inactive metabolites, the dexamethasone preparations have wide adaptation, for example, but not limited by 1, the cases, the various kinds of the injection, the dexamethasone injection, the various eye diseases, the injection, the serum anaphylactoid, the injection, the various eye diseases, the ophthalmopathy, the eye diseases such as the eye diseases, the eye diseases such as the eye diseases, the eye diseases such as the acute septicemia, the acute conjunctivitis, the acute septicemia, the acute papovascleremia, the acute papovascular, the acute septicemia, the acute papovascular, the acute septicemia, the acute papovascular, the acute papova, the acute pap.
Dexamethasone and derivatives thereof have wide application range, strong effect and obvious curative effect, are commonly used glucocorticoids, play a key role in rescuing acute and severe diseases such as allergic diseases, shock, endocrine crisis and the like, and are clinically indispensable medicaments. Dexamethasone has stronger anti-inflammatory action and skin allergy control action than prednisone, the anti-inflammatory activity of 0.75mg of the dexamethasone is equivalent to that of 5mg of prednisone, and the dexamethasone has better effect on skin allergy. For the diseases of the critical conditions such as the continuous state of asthma and the like, the effect of intravenous drip with dexamethasone in large dose can be good in a short period, 5-20 mg can be used for intravenous drip every time, the administration can be repeated for 4-6 h, the dosage is reduced after 48-72 h, and the administration is stopped for 5-7 days. 10mg of the injection can be given to patients with cerebral edema caused by various reasons for the first time. Then, 2-4 mg is injected intramuscularly every 4-6 hours, which can be relieved within 24 hours generally, and the dosage is reduced within 48-72 hours, and the medicine is stopped within 7 days.
Dexamethasone has wide application range, strong effect and obvious curative effect, is a common glucocorticoid, plays a key role in rescuing acute and severe diseases such as allergic diseases, shock, endocrine crisis and the like, and is an indispensable medicament in clinic. Dexamethasone has stronger anti-inflammatory action and skin allergy control action than prednisone, the anti-inflammatory activity of 0.75mg of the dexamethasone is equivalent to that of 5mg of prednisone, and the dexamethasone has better effect on skin allergy. For the diseases of the critical conditions such as the continuous state of asthma and the like, the effect of intravenous drip with dexamethasone in large dose can be good in a short period, 5-20 mg can be used for intravenous drip every time, the administration can be repeated for 4-6 h, the dosage is reduced after 48-72 h, and the administration is stopped for 5-7 days. 10mg of the injection can be given to patients with cerebral edema caused by various reasons for the first time. Then, 2-4 mg is injected intramuscularly every 4-6 hours, which can be relieved within 24 hours generally, and the dosage is reduced within 48-72 hours, and the medicine is stopped within 7 days.
By adopting the formula and the process, the dexamethasone acetate injection prepared by the invention has excellent effect.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art, and the raw materials used are commercially available.
The tablet prescription is listed below, wherein the injection is filled in an amount of 1ml per bottle when being subpackaged, and the amount of each batch of material is not less than 10L when actually feeding, based on the amount of each material in each 1ml of dexamethasone acetate injection.
Example 1: preparation of dexamethasone acetate injection
Prescription:
5mg of dexamethasone acetate,
8mg of sodium chloride,
1.5mg of polysorbate 80,
10 mu g of thimerosal,
5mg of sodium carboxymethylcellulose,
Water for injection was added to 1 ml.
The preparation method comprises the following steps:
(1) adding sodium chloride into water for injection (at 55 ℃) accounting for 75% of the volume of the formula for dissolving;
(2) adding thimerosal into sodium chloride solution, stirring for dissolving, slowly adding sodium carboxymethylcellulose, stirring for dispersing, stirring for dissolving, filtering (with 30 mesh filter screen), heating and boiling;
(3) adding polysorbate 80 and dexamethasone acetate into the boiled solution, continuously boiling for 30min to fully dissolve the liquid medicine, cooling to room temperature, and adding water for injection to 85-90% of the formula volume;
(4) shearing and circulating the liquid medicine obtained in the last step for 45min by using a high-shear homogenizing and emulsifying machine (Guangzhou Yuxiang, the same below), sequentially carrying out medium-pressure (650bar) homogenization and high-pressure (1250bar) homogenization on the liquid medicine in a high-pressure homogenizer (Changzhou super power, the same below), repeatedly carrying out medium-pressure homogenization and high-pressure homogenization alternating treatment until the particle size is less than 15 mu m (the particle number of 15-50 mu m is not more than 3% of the total particle number), adding water to full dose, and filtering (using a filter element with the pore size of 75 mu m and made of polypropylene);
(5) filling the filtrate obtained in the last step into a glass bottle, sealing, and sterilizing under hot pressure (sterilizing at 115 ℃ for 30 minutes) to obtain the product.
Example 2: preparation of dexamethasone acetate injection
Prescription:
dexamethasone acetate 4.5mg,
7.5mg of sodium chloride,
1.6mg of polysorbate 80,
9 mu g of thimerosal,
5.5mg of sodium carboxymethylcellulose,
Water for injection was added to 1 ml.
The preparation method comprises the following steps:
(1) adding sodium chloride into water for injection (at 50 ℃) accounting for 80% of the volume of the formula for dissolving;
(2) adding thimerosal into sodium chloride solution, stirring for dissolving, slowly adding sodium carboxymethylcellulose, stirring for dispersing, stirring for dissolving, filtering (with 30 mesh filter screen), heating and boiling;
(3) adding polysorbate 80 and dexamethasone acetate into the boiled solution, continuously boiling for 35min to fully dissolve the liquid medicine, cooling to room temperature, and adding water for injection to 85-90% of the formula volume;
(4) shearing and circulating the liquid medicine obtained in the last step for 50min by using a high-shear homogenizing emulsifying machine, then sequentially carrying out medium-pressure (800bar) homogenization and high-pressure (1200bar) homogenization on the liquid medicine in a high-pressure homogenizing machine, repeatedly carrying out medium-pressure homogenization and high-pressure homogenization alternate treatment until the particle size is less than 15 micrometers (the particle size of 15-50 micrometers is not more than 3% of the total particle size), adding water to full dose, and filtering (using a filter element with the pore size of 75 micrometers and made of polypropylene);
(5) filling the filtrate obtained in the last step into a glass bottle, sealing, and sterilizing under hot pressure (sterilizing at 115 ℃ for 30 minutes) to obtain the product.
Example 3: preparation of dexamethasone acetate injection
Prescription:
dexamethasone acetate 5.5mg,
8.5mg of sodium chloride,
1.4mg of polysorbate 80,
11 mu g of thimerosal,
4.5mg of sodium carboxymethylcellulose,
Water for injection was added to 1 ml.
The preparation method comprises the following steps:
(1) adding sodium chloride into 70% of the formula volume of water for injection (at the temperature of 60 ℃) to dissolve;
(2) adding thimerosal into sodium chloride solution, stirring for dissolving, slowly adding sodium carboxymethylcellulose, stirring for dispersing, stirring for dissolving, filtering (with 30 mesh filter screen), heating and boiling;
(3) adding polysorbate 80 and dexamethasone acetate into the boiled solution, continuously boiling for 25min to fully dissolve the liquid medicine, cooling to room temperature, and adding water for injection to 85-90% of the formula volume;
(4) shearing and circulating the liquid medicine obtained in the last step for 40min by using a high-shear homogenizing emulsifying machine, then sequentially carrying out medium-pressure (500bar) homogenization and high-pressure (1300bar) homogenization on the liquid medicine in a high-pressure homogenizing machine, repeatedly carrying out medium-pressure homogenization and high-pressure homogenization alternate treatment until the particle size is less than 15 micrometers (the particle size of 15-50 micrometers is not more than 3% of the total particle size), adding water to full dose, and filtering (using a filter element with the pore size of 75 micrometers and made of polypropylene);
(5) filling the filtrate obtained in the last step into a glass bottle, sealing, and sterilizing under hot pressure (sterilizing at 115 ℃ for 30 minutes) to obtain the product.
Example 4: preparation of dexamethasone acetate injection
Prescription:
6mg of dexamethasone acetate,
7mg of sodium chloride,
1.7mg of polysorbate 80,
8 mu g of thimerosal,
6mg of sodium carboxymethyl cellulose,
Water for injection was added to 1 ml.
The preparation method comprises the following steps:
(1) adding sodium chloride into water for injection (temperature 57 ℃) accounting for 73% of the volume of the formula for dissolving;
(2) adding thimerosal into sodium chloride solution, stirring for dissolving, slowly adding sodium carboxymethylcellulose, stirring for dispersing, stirring for dissolving, filtering (with 30 mesh filter screen), heating and boiling;
(3) adding polysorbate 80 and dexamethasone acetate into the boiled solution, continuously boiling for 20min to fully dissolve the liquid medicine, cooling to room temperature, and adding water for injection to 85-90% of the formula volume;
(4) shearing and circulating the liquid medicine obtained in the last step for 30min by using a high-shear homogenizing emulsifying machine, then sequentially carrying out medium-pressure (750bar) homogenization and high-pressure (1220bar) homogenization on the liquid medicine in a high-pressure homogenizing machine, repeatedly carrying out medium-pressure homogenization and high-pressure homogenization alternate treatment until the particle size is less than 15 micrometers (the particle size of 15-50 micrometers is not more than 3% of the total particle size), adding water to full dose, and filtering (using a filter element with the pore size of 75 micrometers and made of polypropylene);
(5) filling the filtrate obtained in the last step into a glass bottle, sealing, and sterilizing under hot pressure (sterilizing at 115 ℃ for 30 minutes) to obtain the product.
Example 5: preparation of dexamethasone acetate injection
Prescription:
dexamethasone acetate 4mg,
9mg of sodium chloride,
1.3mg of polysorbate 80,
12 mu g of thimerosal,
4mg of sodium carboxymethyl cellulose,
Water for injection was added to 1 ml.
The preparation method comprises the following steps:
(1) adding sodium chloride into 78% of formula volume of water for injection (temperature is 52 ℃) to dissolve;
(2) adding thimerosal into sodium chloride solution, stirring for dissolving, slowly adding sodium carboxymethylcellulose, stirring for dispersing, stirring for dissolving, filtering (with 30 mesh filter screen), heating and boiling;
(3) adding polysorbate 80 and dexamethasone acetate into the boiled solution, continuously boiling for 40min to fully dissolve the liquid medicine, cooling to room temperature, and adding water for injection to 85-90% of the formula volume;
(4) shearing and circulating the liquid medicine obtained in the last step for 60min by using a high-shear homogenizing emulsifying machine, then sequentially carrying out medium-pressure (550bar) homogenization and high-pressure (1280bar) homogenization on the liquid medicine in a high-pressure homogenizing machine, repeatedly carrying out medium-pressure homogenization and high-pressure homogenization alternate treatment until the particle size is less than 15 micrometers (the number of particles of 15-50 micrometers is not more than 3% of the total number of particles), adding water to full dose, and filtering (using a filter element with the aperture of 75 micrometers and made of polypropylene);
(5) filling the filtrate obtained in the last step into a glass bottle, sealing, and sterilizing under hot pressure (sterilizing at 115 ℃ for 30 minutes) to obtain the product.
Example 6: with reference to examples 1 to 5, respectively, except that glycine/citric acid was added to the material together with polysorbate 80, and the amounts of the two substances in 5 examples were 4mg/0.75mg, 3mg/1mg, 5mg/0.5mg, 3.5mg/0.6mg, and 4.5mg/0.9mg, respectively, to prepare 5 kinds of injections, which were described as examples 61 to 65, respectively, and the injection prepared in example 6 with reference to example 1 was described as example 61, respectively. Example 7: 3 injections, designated as examples 71 to 73, were prepared by referring to 3 injections of examples 61 to 63, respectively, except that only the corresponding amount of glycine was added without citric acid. Example 8: 3 injections, designated as examples 81 to 83, were prepared by referring to 3 injections of examples 61 to 63, respectively, except that only the corresponding amount of citric acid was added without glycine.
Test example 1: particle size determination of injection
The determination method comprises the following steps: taking a test sample injection, shaking for 30 seconds forcibly, adding a proper amount of glycerol solution (1 → 2) for dilution, sucking the test sample, placing on a glass slide, covering with a cover glass, uniformly distributing particles under light pressure, paying attention to prevent bubbles from mixing, immediately inspecting the whole visual field of the cover glass under a microscope of 50-100 times, and observing whether an agglomeration phenomenon exists or not and whether particles with the particle size of 50 microns or more exist or not (the agglomeration phenomenon should not exist, and the particles with the particle size of 50 microns or more cannot be detected); and then the total number of particles in the field of view of the cover glass (Ma, a field of view for inspecting at least 1000 particles) and the number of particles larger than 15 to 50 μ M in the field of view (M1, large particles) are inspected under a microscope of 200 to 500 times. The macroparticle ratio was calculated as follows:
the large particle ratio was (M1 ÷ M). times.100%
As a result, all the injections obtained in examples 1 to 8 were found to have no aggregation, and no particles having a particle size of 50 μm or more were detected, and the ratio of large particles was found to be in the range of 1.2 to 1.6%, for example, the injection of example 61 had no aggregation, and no particles having a particle size of 50 μm or more were detected, and the ratio of large particles was found to be 1.37%.
Then, the injections were placed in a sealed state in a glass vial in the dark at a temperature of 40 ℃ for 6 months (the placement method is referred to as "high temperature 6 month test" in the present invention, and the data of 0 month and 6 months in the test can be measured, respectively), and the particle size of each injection at 6 months was measured by the same method as described above. Results at 6 months: the coagulation phenomenon does not occur in all injections; particles of 50 μm or more were not detected in all injections; the ratio of the large particles in the total injection solutions obtained in examples 1 to 5 and 7 to 8 was in the range of 8.7 to 11.2%, for example, the ratio of the large particles in the injection solution of example 1 was 9.43%; the ratio of the large particles in the whole injection solution obtained in example 6 was in the range of 1.4 to 2.1%, for example, the ratio of the large particles in the injection solution of example 61 was 1.68%. This result indicates that glycine and citric acid can maintain excellent particle size stability of the suspension injection when they are added simultaneously to the injection, and that excellent particle size physical stability cannot be obtained without adding either of these two agents or with adding only one of them.
Test example 2: inspection and determination of related substances of injection
Referring to a method for inspecting related substances of dexamethasone acetate on page 1530 of the second part of the 'Chinese pharmacopoeia' 2015 edition, the content of dexamethasone as an impurity in 0 month and 6 months of the high-temperature 6-month test of all injection solutions obtained in examples 1-8 is measured.
Each injection is prepared by using the same batch of raw material medicines, and the content of dexamethasone in each injection in 0 month is within the range of 0.07-0.09%. In terms of 6-month data, for each injection, the increase rate of dexamethasone impurity after 6-month treatment was calculated as follows:
dexamethasone increase rate ═ [ (dexamethasone content at 6 months-dexamethasone content at 0 months) ÷ dexamethasone content at 0 months ] × 100%
As a result, the dexamethasone increase rate of all the injection solutions obtained in examples 1-5 and examples 7-8 is in the range of 306-387%, for example, the dexamethasone increase rate of the injection solution in example 1 is 338.8%; the dexamethasone increase rate of all the injection solutions obtained in the embodiment 6 is in the range of 53-96%, for example, the dexamethasone increase rate of the injection solution in the embodiment 1 is 72.4%. This result indicates that the addition of glycine and citric acid to the injection solution at the same time can maintain excellent stability of the content of hydrolyzed impurities in the suspension injection solution, and that the addition of neither of these two agents nor of either agent alone cannot achieve excellent chemical stability.
Test example 3: quality inspection of injection
Referring to the examination method of dexamethasone acetate injection on page 1531 of the second part of the 'Chinese pharmacopoeia' 2015 edition, the main quality indexes of 0 month and 6 months of the high-temperature 6-month test of all the injections obtained in examples 1 to 8 are measured. As a result:
the characteristics are as follows: all injections in 0 month and 6 months accord with the standards of the pharmacopoeia;
pH value: all injections in 0 month and 6 months accord with the pharmacopoeia standard regulation, the pH values are within the range of 4.94-6.12, the addition amount of citric acid is small, the pH values of the injections are not obviously influenced, the data of each sample in 0 month and 6 months basically have no difference and accord with the standard regulation, for example, the pH values of the injections in 0 month and 6 months in example 61 are respectively 5.13 and 5.19%;
content of active ingredient: the data of each sample at 0 month and 6 months are both in the range of 95% to 105% of the indicated amount, for example, the injection of example 61 has a content of 99.3% and 98.9% of the indicated amount at 0 month and 6 months, respectively.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. Dexamethasone acetate injection, which comprises dexamethasone acetate, sodium chloride, polysorbate 80, thimerosal, sodium carboxymethylcellulose and water for injection.
2. The dexamethasone acetate injection according to claim 1, wherein the dexamethasone acetate is present in a concentration of 4-6 mg/ml, such as 4.5-5.5 mg/ml, such as 5 mg/ml.
3. The dexamethasone acetate injection according to claim 1, wherein the concentration of sodium chloride is 7-9 mg/ml, such as 7.5-8.5 mg/ml, such as 8 mg/ml.
4. The dexamethasone acetate injection according to claim 1, wherein the polysorbate 80 concentration is 1.3-1.7 mg/ml, such as 1.4-1.6 mg/ml, such as 1.5 mg/ml.
5. The dexamethasone acetate injection according to claim 1, wherein the concentration of thiomersal is 8-12 μ g/ml, such as 9-11 μ g/ml, such as 10 μ g/ml.
6. Dexamethasone acetate injection according to claim 1, wherein the concentration of sodium carboxymethylcellulose is 4-6 mg/ml, such as 4.5-5.5 mg/ml, such as 5 mg/ml.
7. The dexamethasone acetate injection according to claim 1, comprising:
4-6 mg/ml dexamethasone acetate,
7-9 mg/ml of sodium chloride,
1.3-1.7 mg/ml polysorbate 80,
8-12 mu g/ml of thimerosal,
4-6 mg/ml of sodium carboxymethylcellulose,
Adding 1ml of water for injection; alternatively, the first and second electrodes may be,
which comprises the following steps:
dexamethasone acetate 4.5-5.5 mg/ml,
7.5 to 8.5mg/ml of sodium chloride,
1.4-1.6 mg/ml polysorbate 80,
9-11 mu g/ml of thimerosal,
4.5-5.5 mg/ml of sodium carboxymethylcellulose,
Adding water for injection to 1 ml; alternatively, the first and second electrodes may be,
which comprises the following steps:
5mg of dexamethasone acetate,
8mg of sodium chloride,
1.5mg of polysorbate 80,
10 mu g of thimerosal,
5mg of sodium carboxymethylcellulose,
Water for injection was added to 1 ml.
8. The dexamethasone acetate injection according to claim 1, which is prepared according to a method comprising the following steps:
(1) adding sodium chloride into injection water (for example, at the temperature of 50-60 ℃) with the volume of 70-80% of the formula volume for dissolving;
(2) adding thimerosal into sodium chloride solution, stirring to dissolve, slowly adding sodium carboxymethylcellulose, stirring for dispersing, stirring to dissolve completely, filtering (for example, with 30 mesh sieve), and boiling;
(3) adding polysorbate 80 and dexamethasone acetate into the boiled solution, continuously boiling for 20-40 min to fully dissolve the liquid medicine, cooling to room temperature, and adding water for injection to 85-90% of the formula volume;
(4) shearing and circulating the liquid medicine obtained in the last step for 30-60 min by using a high-shear homogenizing emulsifying machine, then sequentially carrying out medium-pressure (500-800 bar) homogenization and high-pressure (1200-1300 bar) homogenization on the liquid medicine in a high-pressure homogenizing machine, repeatedly carrying out medium-pressure homogenization and high-pressure homogenization alternative treatment until the particle size is less than 15 mu m, adding water to full dose, and filtering (for example, using a filter element with the pore size of 75 mu m and made of polypropylene);
(5) filling the filtrate obtained in the above step into a glass bottle, sealing, and sterilizing under heat and pressure (for example, sterilizing at 115 deg.C for 30 min).
9. The dexamethasone acetate injection according to claim 1, further comprising glycine; for example, the concentration of glycine is 3-5 mg/ml, such as 4 mg/ml; for example, glycine is added with polysorbate 80; and/or, wherein further comprises citric acid; for example, the concentration of citric acid is 0.5-1 mg/ml, such as 0.75 mg/ml; for example, citric acid is added with polysorbate 80.
10. A method for preparing the dexamethasone acetate injection according to any one of claims 1 to 9, comprising the following steps:
(1) adding sodium chloride into injection water (for example, at the temperature of 50-60 ℃) with the volume of 70-80% of the formula volume for dissolving;
(2) adding thimerosal into sodium chloride solution, stirring to dissolve, slowly adding sodium carboxymethylcellulose, stirring for dispersing, stirring to dissolve completely, filtering (for example, with 30 mesh sieve), and boiling;
(3) adding polysorbate 80 and dexamethasone acetate into the boiled solution, continuously boiling for 20-40 min to fully dissolve the liquid medicine, cooling to room temperature, and adding water for injection to 85-90% of the formula volume;
(4) shearing and circulating the liquid medicine obtained in the last step for 30-60 min by using a high-shear homogenizing emulsifying machine, then sequentially carrying out medium-pressure (500-800 bar) homogenization and high-pressure (1200-1300 bar) homogenization on the liquid medicine in a high-pressure homogenizing machine, repeatedly carrying out medium-pressure homogenization and high-pressure homogenization alternative treatment until the particle size is less than 15 mu m, adding water to full dose, and filtering (for example, using a filter element with the pore size of 75 mu m and made of polypropylene);
(5) filling the filtrate obtained in the above step into a glass bottle, sealing, and sterilizing under heat and pressure (for example, sterilizing at 115 deg.C for 30 min).
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